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Antibody-mediated clearance of alphavirus infection from neurons
Parasitology Today, vol. 8, no. 3, 1992
76
nation in September 1989, and 25000 baits were dropped by helicopter in three phases. After each vaccination phase, foxes found dead (or shot by hunters) were collected for rabies diagnosis and bone tetracycline analysis. After the third phase, 81% of inspected foxes were tetracycline-positive. Only one rabid animal was found, but it was at the periphery of the baited area and was tetracycline-negative. No case of livestock rabies was found subsequent
to the second phase of vaccination (notification of cases of rabies in cattle and sheep being mandatory in Belgium), providing an evaluation of the efficacy of this economically viable vaccine programme. Although these results indicate that the vaccine is an effective means of controlling rabies, the authors accept that there are issues still to be resolved. For example, a number of foxes were positive for rabies infection and tetra-
T Cell Memory is Short-lived in the Absence of Antigen D. Gray and P. MatzingerJ. Exp. Med. 174, 969-974 One of the defining characteristics of the immune system is memory of the first encounter with antigen, and three mechanisms have been proposed. The first involves the differentiation of the lymphocyte into a 'memory cell' of very long life span. The second suggests that these memory cells do not live longer, but rather have altered levels of adhesion molecules that make them more easily stimulated by periodic activation by crossreacting environmental antigen. The third mechanism suggests that the original antigen persists in specialized reservoirs, the only known such repository being the surface of follicular dendritic cells (found only in B-cell
follicles). These have been shown to maintain native antigens as antigenantibody complexes for months, if not years. In 1971, Celada suggested the notion of memory loss in the absence of antigen. In 1988, Gray and Skarvall showed that nonreplicating antigen must persist if B-cell memory is to be maintained. In this paper, they show that both helper and cytotoxic T cells keep their ability to generate secondary responses only in the presence of the original priming antigen. To do this, they looked at the decay of memory responses from populations of murine T cells that had been removed from their environment, purified of residual
Antibody-mediated Clearance of Alphavirus Infection from Neurons B. Levine, J.M. Hardwick, B.D. Trapp, T.O. Crawford, R.C. Bollinger and D.E. Griffin Science 254, 856-860 Classically, humoral immunity accounts for the protection of the host against viral infection and neutralization of extracellular virus, while cellular immunity (major histocompatibility complex class-l-restricted lysis of virally infected cells by CD8 + cytotoxic T cells) is responsible for the clearance of infectious virus. This tenet falls apart in the case of the clearance of virus from neurons, because neurons do not express class I molecules, in viva, in response to cytokine stimulation and viral infection. Therefore, a non-MHCrestricted, noncytotoxic immunologic mechanism for the clearance of neuronal viral infection must exist. To study the problem, these workers use a severe combined immunodeficient (SCID) mouse model of Sindbis (SV) infection. SCID mice lack functional B and T cells because of a defect in the T-cell receptor and immunoglobulin gene rearrangement. SV is a single-stranded RNA of the alpha-
virus genus that causes fatal encephalomyelitis in suckling mice and acute, clinically silent encephalomyelitis in weanling mice. It replicates predominantly in neurons. They established that SCID mice develop persistent SV infection, and then investigated the effect of transferred immune T cells and SV hyperimmune serum on the clearance of infectious virus from neural tissues. They found no specific role for cytotoxic T cells or antibody-dependent cytolytic mechanisms in recovery from SV encephalomyelitis, and that clearance of infective virus results from the direct suppression of intracellular viral replication. These findings identify an as yet unknown role for antibodies in recovery from viral infection, and challenge the paradigm of cytotoxic T-cell-mediated clearance. This may reflect a unique immunologic strategy that has evolved to control viral infection in those cells that lack surface MHC expression. •
cycline after the first phase of vaccination (only); they surmise that the foxes were incubating rabies at the time of vaccination. Also, the uptake rate of vaccine by cubs (49%), compared with adults (80%), is below the critical fraction required to prevent the spread of rabies. This is probably a consequence of foraging density, and suggests that vaccination campaigns are more effective in the autumn, when young foxes forage independently. •
antigen and set in adoptive cells for varying lengths of time. For helper T-cell response, they measured the rate and level of antibody produced, in viva, by indicator B cells to the haptencarrier complex, DNP-KLH, and for cytotoxic T cells, they looked for a cytotoxic response to the minor histocompatibility antigen, H-Y, in vitro. Their data further suggest that the memory state is characterized by continuous activation rather than a lengthened life span. This paper is of great interest both in the context of the mounting of an immune response in relation to exposure to parasites, and in that of antiparasite vaccines and duration of a protective response in the absence of boosting through repeated infection. •
Identification of Self Peptides Bound to Purified HLA-B27 T.S. Jardetsky, W.S. Lane, R.A. Robinson, D.R. Madden and D.C. Wiley Nature 3 5 3 , 3 2 6 - 3 2 9 Distinguishing between self and nonself peptides in infected cells is of crucial importance. Class I MHC molecules bind and transport intracellular peptides to the cell surface where cytotoxic T cells analyse the cargo: self peptides are tolerated but nonself peptides from, say, virally infected cells are recognized and the infected cell is lysed. The authors report the sequences of I I self peptides, all nonamers, that are bound to the human class I MHC molecule, HLA-B27. Seven of these peptides can be seen to derive from cytosolic or nuclear proteins, such as histone, ribosomal proteins, and members of the 90K heatshock protein family. •
Outlook is compiled by T. Saklatvalafrom suggestions by A.F. Bianco, P.H. David and S.L.James.
76
nation in September 1989, and 25000 baits were dropped by helicopter in three phases. After each vaccination phase, foxes found dead (or shot by hunters) were collected for rabies diagnosis and bone tetracycline analysis. After the third phase, 81% of inspected foxes were tetracycline-positive. Only one rabid animal was found, but it was at the periphery of the baited area and was tetracycline-negative. No case of livestock rabies was found subsequent
to the second phase of vaccination (notification of cases of rabies in cattle and sheep being mandatory in Belgium), providing an evaluation of the efficacy of this economically viable vaccine programme. Although these results indicate that the vaccine is an effective means of controlling rabies, the authors accept that there are issues still to be resolved. For example, a number of foxes were positive for rabies infection and tetra-
T Cell Memory is Short-lived in the Absence of Antigen D. Gray and P. MatzingerJ. Exp. Med. 174, 969-974 One of the defining characteristics of the immune system is memory of the first encounter with antigen, and three mechanisms have been proposed. The first involves the differentiation of the lymphocyte into a 'memory cell' of very long life span. The second suggests that these memory cells do not live longer, but rather have altered levels of adhesion molecules that make them more easily stimulated by periodic activation by crossreacting environmental antigen. The third mechanism suggests that the original antigen persists in specialized reservoirs, the only known such repository being the surface of follicular dendritic cells (found only in B-cell
follicles). These have been shown to maintain native antigens as antigenantibody complexes for months, if not years. In 1971, Celada suggested the notion of memory loss in the absence of antigen. In 1988, Gray and Skarvall showed that nonreplicating antigen must persist if B-cell memory is to be maintained. In this paper, they show that both helper and cytotoxic T cells keep their ability to generate secondary responses only in the presence of the original priming antigen. To do this, they looked at the decay of memory responses from populations of murine T cells that had been removed from their environment, purified of residual
Antibody-mediated Clearance of Alphavirus Infection from Neurons B. Levine, J.M. Hardwick, B.D. Trapp, T.O. Crawford, R.C. Bollinger and D.E. Griffin Science 254, 856-860 Classically, humoral immunity accounts for the protection of the host against viral infection and neutralization of extracellular virus, while cellular immunity (major histocompatibility complex class-l-restricted lysis of virally infected cells by CD8 + cytotoxic T cells) is responsible for the clearance of infectious virus. This tenet falls apart in the case of the clearance of virus from neurons, because neurons do not express class I molecules, in viva, in response to cytokine stimulation and viral infection. Therefore, a non-MHCrestricted, noncytotoxic immunologic mechanism for the clearance of neuronal viral infection must exist. To study the problem, these workers use a severe combined immunodeficient (SCID) mouse model of Sindbis (SV) infection. SCID mice lack functional B and T cells because of a defect in the T-cell receptor and immunoglobulin gene rearrangement. SV is a single-stranded RNA of the alpha-
virus genus that causes fatal encephalomyelitis in suckling mice and acute, clinically silent encephalomyelitis in weanling mice. It replicates predominantly in neurons. They established that SCID mice develop persistent SV infection, and then investigated the effect of transferred immune T cells and SV hyperimmune serum on the clearance of infectious virus from neural tissues. They found no specific role for cytotoxic T cells or antibody-dependent cytolytic mechanisms in recovery from SV encephalomyelitis, and that clearance of infective virus results from the direct suppression of intracellular viral replication. These findings identify an as yet unknown role for antibodies in recovery from viral infection, and challenge the paradigm of cytotoxic T-cell-mediated clearance. This may reflect a unique immunologic strategy that has evolved to control viral infection in those cells that lack surface MHC expression. •
cycline after the first phase of vaccination (only); they surmise that the foxes were incubating rabies at the time of vaccination. Also, the uptake rate of vaccine by cubs (49%), compared with adults (80%), is below the critical fraction required to prevent the spread of rabies. This is probably a consequence of foraging density, and suggests that vaccination campaigns are more effective in the autumn, when young foxes forage independently. •
antigen and set in adoptive cells for varying lengths of time. For helper T-cell response, they measured the rate and level of antibody produced, in viva, by indicator B cells to the haptencarrier complex, DNP-KLH, and for cytotoxic T cells, they looked for a cytotoxic response to the minor histocompatibility antigen, H-Y, in vitro. Their data further suggest that the memory state is characterized by continuous activation rather than a lengthened life span. This paper is of great interest both in the context of the mounting of an immune response in relation to exposure to parasites, and in that of antiparasite vaccines and duration of a protective response in the absence of boosting through repeated infection. •
Identification of Self Peptides Bound to Purified HLA-B27 T.S. Jardetsky, W.S. Lane, R.A. Robinson, D.R. Madden and D.C. Wiley Nature 3 5 3 , 3 2 6 - 3 2 9 Distinguishing between self and nonself peptides in infected cells is of crucial importance. Class I MHC molecules bind and transport intracellular peptides to the cell surface where cytotoxic T cells analyse the cargo: self peptides are tolerated but nonself peptides from, say, virally infected cells are recognized and the infected cell is lysed. The authors report the sequences of I I self peptides, all nonamers, that are bound to the human class I MHC molecule, HLA-B27. Seven of these peptides can be seen to derive from cytosolic or nuclear proteins, such as histone, ribosomal proteins, and members of the 90K heatshock protein family. •
Outlook is compiled by T. Saklatvalafrom suggestions by A.F. Bianco, P.H. David and S.L.James.