Delayed progression of a murine retrovirus-induced acquired immunodeficiency syndrome in X-linked immunodeficient mice.

Abstract

Stlmmal~The murine acquired immunodeficiency syndrome (MAIDS) caused by defective LP-BM5 murine leukemia virus (MuLV) is a disease that shows severe immunodeficiency with abnormal lymphoproliferation, and hypergammaglobulinemia in susceptible C57BL/6 (B6) mice. To examine the cellular mechanisms of development of MAIDS, we injected LP-BM5 MuLV intraperitoneaUy into B6 mice bearing the X chromosome-linked immunodefidency (xid). xid mice lack functionally mature B cells including Ly-1 B cells (also known as B-1 cells). All B6 mice died by 20 wk after LP-BM5 MuLV inoculation. In marked contrast, xid mice have continued to survive without any sign of MAIDS-related symptoms till at least 20 wk after the inoculation. The delayed progression of MAIDS in x/d mice appears to depend on xid mutation, according to our experiments using both sexes of (B6.xid x B6)F1 and (B6 x B6.xid)F1 mice. Furthermore, Ly-1 B cells, enriched by a FACS | were shown to integrate the defective genome and appeared to be a major virus-infected B cell population. Our data corroborate that Ly-1 B cells play an important role in the induction and progression of MAIDS.T he murine acquired immunodeficiency syndrome (MAIDS) 1 caused by a defective retrovirus (defective LP-BM5 murine leukemia virus [MuLV]) (1, 2), which encodes a gag fusion protein (Pr60S~s), is a disease that shows many similarities with human AIDS, in particular abnormal lymphoproliferation, polyclonal B cell activation, and severe immunodeficiency (3, 4). Previous studies have proven that complex cellular interactions between T and B cells are required for the induction and development of MAIDS. B cell abnormalities are shown in the presence of T cells of CD4 phenotype (5), whereas B cells are required for induction of phenotypic and functional T cell abnormalities in MAIDS (6). It is interesting that a recent study reported that the majority of cells infected with the defective LP-BM5 MuLV 1 Abbrrviations used in this paper: MAIDS, murine acquired immunodeficiency syndrome; MuLV, murine leukemia virus; xid, X-linked immunodeficiency.belongs to B cell lineages (7,8), implying that B cells trigger the induction and development of MAIDS. The development of hypergammaglobulinemia in MAIDS also suggests that B cell activation and its differentiation is associated with the induction of MAIDS.It still remains obscure, however, what kinds orB cell subsets are required for and involved in the induction and development of MAIDS. To examine these problems, we used the X-linked immunodeficient (xic 0 mice (9-12). The defects in x/d mice, which show the impaired humoral immune response to type II T cell independent antigens (9, 10, 12), has been implicated in the arrest of functional maturation of B cells. In particular, the lack of Ly-1 B cells (also known as B-1 cells [13]) is noticed in xid mice (11).Here we report that xid mice are resistant to MAIDS and Ly-1 B cells are a major virus-infected B cell population. Our data corroborate that Ly-1 B cells play an important role in the developme...

Characterization of the CD154-Positive and CD40-Positive Cellular Subsets Required for Pathogenesis in Retrovirus-Induced Murine Immunodeficiency

“…Thus, it would appear from our data that this latter B-la subset of B cells is not essential as the cellular basis of the CD40 requirement in MAIDS. This finding is relevant to the ongoing debate as to the importance of B-la B cells in MAIDS pathogenesis (20,50). Our data clearly imply that if B-la B cells have any role in MAIDS pathogenesis, then at least this putative function does not depend on the expression of CD40.…”

Cells and cytokines in the pathogenesis of MAIDS, a retrovirus-induced immunodeficiency syndrome of mice

“…Recently, it was found that B6 or P strain mice bearing the xid mutation develop MAIDS with a markedly prolonged time course ([18] and Y. Tang, W. Kim, K. Holmes, A. Hiigin, J. Hartley, and H. Morse, submitted for publication]. The observations of Hitoshi et al [18] that CD5 § B cells are expanded in normal infected mice suggested that a deficit of CD5 § B cells in xid was responsible for delayed disease. In support of this view, it was reported that the B cell repertoire of infected mice was biased toward that expressed by CD5 § B cells [51]; however, we have found that xid mice inoculated with normal spleen cells develop MAIDS within 10 weeks of infection (Y. Tang et al, submitted for publication).…”

Role of IP-10/CXCL10 in the progression of pancreatitis-like injury in mice after murine retroviral infection

“…These examples suggest that if the organ of the specific lesions induced by a particular infection was the same as the target organ of the infectious agent, IP-10 neutralization could ameliorate the organ lesions by inhibiting the trafficking of effector cells that eliminate the infectious agents from the target organ. In MAIDS, we reported previously that the virus was integrated in Ly-1 B cells but not in T cells (9) or on parenchymal cells of the pancreas (unpublished observations), although several reports have shown that B cells (13) and macrophages (4) as well as T cells (15) can serve as targets for infection of the virus. Therefore, pancreatic tissues are not the direct target cells of LP-BM5 infection, and the IP-10 neutralization-induced amelioration of pancreatic lesions of MAIDS cannot be explained by the decreased accumulation of effector cells that eliminate LP-BM5 from the pancreas.…”