Pathogenesis of infectious bursal disease

Natural IBDV infection occurs by the oral route. Other mucosal routes have been demonstratedfor experimental IBDV infection. The mononuclear phagocytic cells and lymphoid cells of the gut mucosa may serve as targets for IBDV infection and replication (MÜLLER et al. 1979). Infected macrophages transport the virus to the bursa of Fabricius (BF), the prime target organ for extensive IBDV replication in the cytoplasm of intrabursal IgM+ B-cells (KAUFER u. WEISS 1980; HIRAGA et al.

1994). Virus dissemination to other lymphoid organs such as to the thymus, bone marrow, spleen, Peyer's patches, cecal tonsils, and Harderian glands may take place

mainly during vvIBDV infection of susceptible chickens (ETERRADOSSI u. SAIF 2008). The cecal tonsils and bone marrow may serve as non-bursal lymphoid tissues supporting virus replication at later time points (ELANKUMARAN et al. 2002).

As early as 48 hr pi, IBDV infection induces prominent inflammation in the BF. By day 3 to 4 pi, all bursal IgM+ B-cells are infected and show cytolytic changes (CHEVILLE 1967). vvIBDV strains such as UK661 can infect Bu-1+ cells and IgY+ B-cells in several lymphoid tissues indicating both immature and mature B-cells can be infected (WILLIAMS u. DAVISON 2005), whereas classical virulent and variant IBDVs mostly target immature B-cells. Between 7 and 21 dpi, IBDV infection results in significant reduction in the number of the B subpopulation compared to the A subpopulation of IgM+ B-cells as determined by flow cytometric analysis (PETKOV et al. 2009). These two phenotypes differed on their cell size and granularity as well as showed differential expression levels of Lewis(x), IgM, Bu-1b, and MUI78 surface antigens. It becomes apparent that macrophages are infected with IBDV and in vitro studies indicated rapid virus replication with altered in vitro phagocytic activity of such cells (KHATRI u. SHARMA 2009b). Other cells like the bone marrow-derived mesenchymal stem cells may be infected with IBDV (KHATRI u. SHARMA 2009b).

The haemopoietically derived reticular cells, which reside in the antigen-trapping zone of the spleen (ellipsoid and periellipsoidal white pulp), were found to be more susceptible to IBDV. The reticular cells of mesenchymal origin, which reside in the bursal cortex, and periarteriolar lymphoid sheaths, germinal center (GC) and red pulp of the spleen were relatively resistant to IBDV (BIRO et al. 2011). Bursal follicular dendritic cells disappeared during IBDV infection probably due to lack of an intact B-cell microenvironment (JEURISSEN et al. 1998; KABELL et al. 2006).

Generally, the sequellae of IBDV infections such as severity of clinical signs, organ lesions and immunosuppression correlate with the status of immunity, age and genetic background of affected chickens and with the virulence of the infecting virus strain (BERG 2000). SPF chickens infected with vvIBDV develop an earlier onset of mortality and more severe bursal lesions compared to broiler chickens with MAB and vaccinated chickens (HASSAN et al. 2002; ARICIBASI et al. 2010). Infections by

virulent IBDV resulted in an earlier onset and higher production of IFN-γ in the bursa of young SPF chickens compared to their older counterpart. Massive interferon-γ (IFN-γ) production from T-cells infiltrating the bursa during an acute IBDV infection (ELDAGHAYES et al. 2006; RAUW et al. 2007) further activates macrophages to release proinflammatory cytokines such as interleukin-6 (IL-6) and also nitric oxide (NO), which may aggravate bursal lesions (KIM et al. 1998). IFN-γ is suggested to be a potent apoptosis inducer in IBDV infected or adjacent healthy B-cells (LAM 1997;

TANIMURA u. SHARMA 1998). A massive mast cell influx detected in the bursa of SPF chickens infected with vvIBDV may aggravate bursal lesions as typical indicators of acute hypersensitivity responses were observed in the bursa of such chickens (WANG et al. 2008; WANG et al. 2012a). These cytokine mediated bursal lesions may result in an early onset of severe immunosuppression in younger chickens (RAUTENSCHLEIN et al. 2007). Similar patterns of cytokine production and bursal lesions were detected in SPF layer type chickens infected with virulent IBDV compared to infection of age-matched 3 weeks old broiler type chickens (ARICIBASI et al. 2010).

Bursal lesions with B-cell depletions lead to severe humoral immunosuppression (SHARMA et al. 1994; SHARMA et al. 2000). When susceptible neonatal chickens younger than two weeks of age are infected, they may lose the entire bursal B-cells, which result in permanent immunologic damage (HUDSON et al. 1975; WITHERS et al. 2005). Cytokine dysregulation may cause suppression of innate and cellular immunity (RAUW et al. 2007). This was elucidated as recombinant chicken IFN-γ (rchIFN-γ) inhibited an in vitro proliferation of naïve peripheral blood lymphocytes (PBL) or splenocytes (RAUW et al. 2007). Lymphocytes harvested from the blood and lymphoid organs of an IBDV infected or live IBDV vaccinated chickens showed reduced lymphoproliferative responses when stimulated by conventional mitogens (MAZARIEGOS et al. 1990; SHARMA et al. 2000). This inhibition has been detected during early time points after IBDV infection coinciding with an increased IFN-γ response. Recently, in vitro study described the interaction of IBDV VP4 with the chicken glucocorticoid-induced leucine zipper (cGILZ) that inhibited the transcription

of NF-κB with a subsequent suppression of the innate immunity (LI et al. 2013b).

Others suggested T-cells with regulatory property may mediate cellular immunosuppression (KIM et al. 1998; SHANMUGASUNDARAM u. SELVARAJ 2011). IBDV infection induced mucosal immunosuppression denoted by reduced intraepithelial lymphocytes (iIELs) and their in vitro cytotoxicity activity (KUMAR et al.

1998). A reduced intestinal secretory IgA+ B-cells were also detected (WANG et al.

2009a).

The immunological functions of both B- and T-cells may be restored during recovery of infected chickens (KIM et al. 1999; SHARMA et al. 2000). The mechanisms of B-cell functional restoration were described, whereas of T-B-cells remained unclear.

Bursal stem cells, which survive IBDV-induced depletion, proliferate to generate new and larger bursal follicles. They became repopulated with IgM+ B-cells, and Bu-1+

cells expressing IgM or IgY (WILLIAMS u. DAVISON 2005) and dendritic-like cells (WITHERS et al. 2005). The B-cells in these follicles may undergo immunoglobulin (Ig) gene (hyper)conversion for Ig diversity and sustain specific immunological functions (WITHERS et al. 2005; WITHERS et al. 2006). Previous study indicated the strong expression of the Le^x and chB1 genes in the recovering follicles as indicators of Ig gene (hyper)conversion (IVAN et al. 2001). Medullary B-cells surviving IBDV infection form small follicles, which lack Ig gene (hyper)conversion. Birds with only small follicles do not produce Abs against IBDV or other Ags, and such chickens may be in a state of permanent immunosuppression (WITHERS et al. 2006).