L H Perrin’s scientific contributions

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Publications (10)


Lysis of measles virus-infected cells by the purified cytolytic alternative complement pathway and antibody
  • Article
  • Full-text available

October 1979

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20 Reads

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71 Citations

J G Patrick Sissons

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R D Schreiber

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L H Perrin

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[...]

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M. B. A. Oldstone

The dependence of antibody-and-complement-mediated lysis of virus-infected cells on the alternative pathway was examined utilizing the isolated cytolytic alternative pathway--a system consisting of the six purified proteins of the alternative pathway of activation (C3, factors B and D, beta 1H, C3b inactivator and properdin), and the five proteins of the membrane attack pathway (C5--9) of complement. HeLa cells acutely infected with measles virus were lysed by anti-viral IgG and the isolated cytolytic alternative pathway with an efficiency comparable to whole human serum. IgG and its F(ab')2 fragment were equally effective in inducing lysis by the isolated cytolytic alternative pathway, binding of approximately equal to 5 X 10(7) molecules per cell being required for 50% lysis; in contrast, no lysis occurred when equivalen or greater amounts of Fab' were bound to the virus-infected cell. Properdin was required for lysis. No lysis occurred if properdin was deleted from the isolated cytolytic alternative pathway, and lysis was diminished by 80% in properdin-depleted serum. Uptake of [125I]C3b from the isolated alternative pathway onto measles virus-infected cells occurred in the absence of properdin, but was accelerated in the presence of properdin. The 11 proteins of the isolated cytolytic alternative pathway are thus sufficient for lysis of measles virus-infected cells bearing anti-viral IgG or F(ab')2 without any other serum protein.

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Generation of virus-specific cytolytic activity in human peripheral lymphocytes after vaccination with vaccinia virus and measles virus

December 1978

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3 Reads

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10 Citations

Medical Microbiology and Immunology

Human peripheral blood lymphocytes (PBL) harvested after vaccination with vaccinia or measles virus showed a specific activity against virus-infected target cells. This activity peaked on day 7 and was specific for the target cells infected with the virus used for the vaccination. The cytotoxic activity was not related to HLA markers. The cells involved in the cytolytic process were lymphocytes bearing Fc receptors. In addition, the cytotoxic activity was abrogated by more than 90% by rabbit Fab'2 anti-human IgG. It is therefore likely that two subpopulations of lymphocytes are involved: an antibody-secreting cell providing specific antiviral antibody and an effector cell bearing Fc receptor (K cells). Finally, these experiments suggest that antibody-dependent cell cytotoxicity may play a major role in the recovery from virus infection in man.


Immune response in humans after vaccination with vaccinia virus: Generation of a virus-specific cytotoxic activity by human peripheral lymphocytes

November 1977

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6 Reads

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90 Citations

After vaccinia virus vaccination of human volunteers, local indurations developed within 10 days, and regional adenopathy was detected in half of the individuals. Their peripheral blood lymphocytes (PBL) harvested at different days after vaccination showed specific activity against target cells infected with vaccinia virus with a peak activity at day 7. The specificity of the cytotoxic activity was not related to HLA markers, since autologous, homologous, and heterologous infected target cells were lysed with the same efficiency. The cytotoxic activity was caused by PBL that did not rosette with sheep erythrocytes and could be depleted by more than 90 percent by removing Fc receptor-bearing cells. T-cell- depleted PBL showed a one-half to two times greater cytotoxicity than intact PBL. The cytotoxic activity could also be abrogated by more than 95 percent by rabbit Fab(2) anti-human IgG. On the other hand, nonimmune PBL lysed vaccinia-infected target cells in the presence of specific antibodies against vaccinia virus, thus demonstrating that ADCC could be efficient in lysing vaccinia-infected target cells. We conclude that after vaccination, antibody-forming cells arise and provide specific anti-viral antibody and that the cytotoxic cells detected in this reaction are K cells. These experiments suggest that antibody-dependent cell cytotoxicity may be of major importance in the recovery of man to virus infections.


The Formation and Fate of Virus Antigen-Antibody Complexes

February 1977

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10 Reads

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34 Citations

The Journal of Immunology

We report the fate of 125I human IgG measles virus antibodies complexed to virus antigens expressed on the surfaces of HeLa cells persistently infected with measles virus. Each HeLa cell expressing viral antigens on its surface bound about 7.5 x 106 IgG molecules under saturation conditions. Three hours after 125I antiviral IgG bound to and saturated all antigenic sites on infected cells, 30% of the counts were released (85% TCA ppt), after 12 hr 60%, and after 24 hr 75% (30% TCA ppt). By linear sucrose density centrifugation about 30% of the counts released from infected cells at 3 hr sedimented faster than 7S IgG, 60% sedimented at the 7S position whereas 10% (non-TCA ppt) were found at the top of the gradient. Using specific rabbit antibody to measles virus hamagglutinin or nucleocapsid, we found that hemagglutinin, but not nucleocapsid antigen, was present in the heavy complexes. These experiments show that after anti-measles virus antibody binds to cell surface measles viral antigens (i.e.. hemagglutinin), immune complexes form and are shed into culture fluids. In addition part of immune complex is endocytosed and broken into small m.w. components. Shedding of virus antigen-antibody complexes from the cell's surface may be an important source of the circulating complexes found in virus-infected humans and animals.


Immunologic Injury in Measles Virus Infection III. Presence and Characterization of Human Cytotoxic Lymphocytes

February 1977

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4 Reads

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87 Citations

The Journal of Immunology

Human peripheral blood leukocytes (PBL) from patients with chronic measles virus infection (SSPE) or from immune, adult humans (convalescent from acute childhood measles virus infection) are cytotoxic for target cells infected with measles virus as measured by a 51Cr assay. Specific release of 51Cr by immune PBL occurred both with and without human antibodies added to measles virus infected cultures. Maximal killing in the absence of added antibodies to measles virus was usually detected only after 15 to 18 hr of incubation and with a high PBL to target ratio (100:1). When antibody to measles virus was added, PBL mediated killing of virus infected cells was not blocked. Instead, killing was enhanced and maximal lysis occurred with fewer PBL and a shorter incubation time. This cytotoxic reaction was inhibited in dose response manner upon the addition of Fab fragments of IgG containing antibodies to measles virus. On the average 4 to 5x105 antibody molecules bound per infected target cell before initiation of antibody enhanced PBL killing. Depletion of either glass adhering or E rosette forming cells did not reduce PBL killing of measles virus infected target cells in either system. In contrast, removal of non E rosette or of EAC rosette forming population of PBL almost completely abrogated cytotoxicity. When Fc bearing cells were removed, killing of virus infected target cells was concomitantly reduced. Lysis of measles virus infected target cells did not require histocompatibility between the PBL and the target cell. Further, immunospecific lymphocyte killing was not enhanced by such a histocompatibility fit. These experiments indicate first, that the effector PBL involved in lysis of measles virus infected targets are not T cells but are probably K cells and, second, that PBL obtained from patients with SSPE are competent in killing measles virus infected targets. Moreover, sera from SSPE patients did not contain a factor(s) that blocked PBL mediated cytotoxicity.


Immunologic Injury in Measles Virus Infection

January 1977

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1 Read

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24 Citations

The Journal of Immunology

Human peripheral blood leukocytes (PBL) from patients with chronic measles virus infection (SSPE) or from immune, adult humans (convalescent from acute childhood measles virus infection) are cytotoxic for target cells infected with measles virus as measured by a 51Cr assay. Specific release of 51Cr by immune PBL occurred both with and without human antibodies added to measles virus-infected cultures. Maximal killing in the absence of added antibodies to measles virus was usually detected only after 15 to 18 hr of incubation and with a high PBL to target ratio (100:1). When antibody to measles virus was added, PBL-mediated killing of virus-infected cells was not blocked. Instead, killing was enhanced and maximal lysis occurred with fewer PBL and a shorter incubation time. This cytotoxic reaction was inhibited in a dose-response manner upon the addition of Fab fragments of IgG containing antibodies to measles virus. On the average 4 to 5 × 105 antibody molecules bound per infected target cell before initiation of antibody-enhanced PBL killing. Depletion of either glass-adhering or E-rosette-forming cells did not reduce PBL killing of measles virus-infected target cells in either system. In contrast, removal of non-E rosette or of EAC rosette-forming population of PBL almost completely abrogated cytotoxicity. When Fc-bearing cells were removed, killing of virus-infected target cells was concomitantly reduced. Lysis of measles virus-infected target cells did not require histocompatibility between the PBL and the target cell. Further, immunospecific lymphocyte killing was not enhanced by such a histocompatibility fit. These experiments indicate first, that the effector PBL involved in lysis of measles virus-infected targets are not T cells but are probably K cells and, second, that PBL obtained from patients with SSPE are competent in killing measles virus-infected targets. Moreover, sera from SSPE patients did not contain a factor(s) that blocked PBL-mediated cytotoxicity.


Evidence of immune complex formation in patients with amyotrophic lateral sclerosis

August 1976

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13 Reads

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68 Citations

The Lancet

Immune complexes have been found in several chronic diseases of unknown aetiology and identification of the constituents of the complexes might lead to recognition of aetiological agents. Sera and renal tissues from patients with amyotrophic lateral sclerosis (A.L.S.) were studied for evidence of immune complexes. C1q precipitation testing demonstrated that sera from 10 of 25 patients with classic A.L.S. bound significantly more radiolabelled C1q than sera from 15 controls. In renal glomeruli studied for deposition of host 1gG, C3, fibrinogen, and albumin by means of direct immunofluorescence, 9 of 33 patients with A.L.S. (27 biopsy and 6 necropsy specimens) had moderate amounts of both IgG and C3 of granular basement membrane and mesangia. This pattern of immunofluorescence is characteristic of immune complex deposits. Of these 9, 8 had rapidly progressive neurological courses, whereas among the remaining 18 patients with no evidence of immune-complex disease, 9 of 12 available for clinical follow-up had stable or slowly progressive courses.


C Dependent Immune Lysis of Virus Altered Plasma Membranes: Dependence on the Alternative C Pathway and Factor B

June 1976

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2 Reads

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1 Citation

The Journal of Immunology

Antibody-mediated C dependent lysis of cell lines infected with herpes type 1 (HeLa cells), herpes type 2 (HeLa), influenza Å (Chang), measles (HeLa) and mumps (Vero) were analyzed for C participation. Lysis occurred with immune human sera, Mg++ EDTA immune sera, and immune sera depleted of C4 or treated with Fab anti-C4. Lysis did not occur with non-immune sera, Mg++EDTA sera, sera heated 50°C for 25 min, sera depleted of Factor B, or sera treated with Fab anti-Factor B. Lysis was restored to heated sera and Factor B immunodepleted sera by addition of Factor B but not by C2. Properdin and Factor D depleted immune sera lost significant lytic activity, but to a lesser extent than serum depleted of Factor B. Addition of depleted factors in physiologic concentrations partially restored the lytic activity. Further studies showed that lysis of measles infected HeLa cells was induced by both immune IgG and F(ab')2 but not Fab' in the presence of a non-antibody containing human C source.


Mechanism of injury of virus infected cells by antiviral antibody and complement: participation of IgG, F(ab')2, and the alternative complement pathway

June 1976

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15 Reads

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98 Citations

Journal of Experimental Medicine (JEM)

Antibody-mediated C-dependent lysis of cell lines infected with herpes simplex type 1 virus, influenza A degrees virus, measles virus, and mumps virus occurred by the alternative C pathway with the participation of IgG antibodies. Lysis occurred only with immune human sera, Mg++ EGTA immune sera, and immune sera depleted of C4 or treated with Fab anti-C4. Lysis did not occur with nonimmune sera, Mg++ EDTA immune sera, and immune sera heated 50 degrees C for 25 min, depleted of factor B or treated with Fab antifactor B. Lysis was restored to heated and factor B immunodepleted immune sera by addition of factor B, but not by addition of an excess of C2. Further studies showed that lysis of HeLa cells infected with measles virus was induced by both immune IgG and F(ab')2 but not Fab' in the presence of a nonantibody-containing human C source. Lysis of measles virus-infected cells was also indpendent of movement of viral antigens on the surface of the infected cells, as inhibition of viral antigen capping by cytochalasin B or sodium azide was not associated with abrogation of immune lysis.


Measurement of Virus Antigens on the Surfaces of HeLa Cells Persistently Infected with Wild Type and Vaccine Strains of Measles Virus by Radioimmune Assay

April 1976

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8 Reads

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31 Citations

Journal of General Virology

Persistent states of measles virus infection have been established in HeLa cells by using Edmonston strain virus and two types of measles virus vaccine (M-VAC and Schwarz). The absolute amount of surface viral antigens expressed on these cells infected separately with the three viruses has been assessed by a newly developed method which employs [125I]-labelled Fab fragments of immunoglobulin G (IgG) from immune human sera. This method was used to determine the level of viral antigenic expression on acutely infected HeLa cells harvested at a time when 95 to 100% of cells could be lysed by antiviral antibody and complement. From our data, more than 1 X 10(6) antibody molecules must bind to each cell infected with measles virus before complement dependent lysis can occur in a homologous test system. Persistently infected cells bind 2 to 3 times less antibody than acutely infected cells and correspondingly exhibit less susceptibility to humorally-mediated immune lysis.

Citations (9)


... Specific humoral immune function is demonstrated by high levels of circulating and locally produced antibody [18]. The presence of cell-mediated cytotoxicity against measles-infected targets has been demonstrated in vitro [26,27,28]. How then does the virus survive in the face of specific effector capability? ...

Reference:

Types of immunological failure in the 'slow virus' encephalopathies and multiple sclerosis
Immunologic Injury in Measles Virus Infection
  • Citing Article
  • January 1977

The Journal of Immunology

... However, increasing evidence supports the presence of autoimmune mechanisms that contribute to ALS pathogenesis, such as pharmacological, biochemical, and physiological studies, are performed in animal models and in cell cultures [5,6]. Studies have also reported typical hallmarks of autoimmunity, such as the presence of circulating immune complexes, the association with other autoimmune conditions, and the evidence of higher frequency of specific histocompatibility types [7]. ...

Evidence of immune complex formation in patients with amyotrophic lateral sclerosis
  • Citing Article
  • August 1976

The Lancet

... An effective innate immune defense, therefore, must target both phases of the virus life cycle. Notably, all the major complement pathways-classical, alternative, and lectin-are potent in targeting cell-free viral particles as well as the virus-infected cells [34][35][36][37]. Moreover, as stated above, the system also boosts other antiviral innate [9] and acquired immune responses [7,8] to limit the viral infection. ...

Mechanism of injury of virus infected cells by antiviral antibody and complement: participation of IgG, F(ab')2, and the alternative complement pathway

Journal of Experimental Medicine (JEM)

... Moreover, anti-vaccinia virus antiserum added to infected fibroblasts drastically improved the ability of non-immune Fc R PBL to lyse these cells, but not uninfected cells. Following vaccination of footpad to adult rabbits with SFV (Madison or Patuxent strain), researchers identified ADCC in another poxvirus infections, Scott et al. [57] and increasing of T-cell and B cell proliferation in draining lymph node and spleen respectively. In addition, one more study revealed in mice that, the production of ectromelia virus-specific antibodies occurs too delayed to give defense by ADCC from a lethal primary infection in certain mouse strains [58][59][60], however, Upon reinfection, humoral antibody and ADCC are believed to be a significant resistant mechanism [61]. ...

Immune response in humans after vaccination with vaccinia virus: Generation of a virus-specific cytotoxic activity by human peripheral lymphocytes

... Early reports demonstrated antibody-mediated lysis of virus-infected cells by serum depleted of, or deficient in, C2 or C4, whereas this ability was not retained in Factor-B-depleted serum (Joseph et al., 1975). Moreover, these findings were confirmed using purified components of the alternative pathway, excluding the contribution of other pathways via a bypass mechanism (Patrick Sissons et al., 1979). Lysis by the alternative pathway was only seen when IgG or Fab was bound to these cells, and these antibodies did not initiate complement activation by themselves (Sissons et al., 1980). ...

Lysis of measles virus-infected cells by the purified cytolytic alternative complement pathway and antibody

... An example of historical significance is that respiratory smallpox infection of humans leads to approximately 30% mortality, whereas deliberate smallpox inoculation into the skin results in only 0.5% to l% mortality and yet provides full protection against later smallpox exposure. In terms of differences in host species -specific immunity, one group analyzed the cellular immune responses mounted against vaccinia virus in both mice [15] and humans [16,17] by measuring direct ex vivo cytolytic activity against autologous vaccinia-infected target cells. In mice, strong direct ex vivo lytic activity was mediated primarily by major histocompatibility complex (MHC)-restricted T-cells, whereas in humans, direct ex vivo lytic activity was not MHC-restricted, could not be demonstrated in purified T-cell fractions, and instead was found to be mediated almost entirely by natural killer cells through antibody-dependent cell cytotoxicity. ...

Generation of virus-specific cytolytic activity in human peripheral lymphocytes after vaccination with vaccinia virus and measles virus
  • Citing Article
  • December 1978

Medical Microbiology and Immunology

... Thus, the antibodies produced by these B-cells undergo proliferation [27]. Finally, Process (6) signifies the degradation of virus-antibody complexes, which can be recognized and rapidly degraded by functional immune cells like natural killer cells [28]. ...

The Formation and Fate of Virus Antigen-Antibody Complexes
  • Citing Article
  • February 1977

The Journal of Immunology

... The interaction between antibodies and Fc receptors on cytotoxic effector cells, such as monocytes/macrophages, polymorphonuclear leukocytes, T-cells and natural killer (NK) cells, induces a signal transduction cascade in the effector cells which ultimately leads to destruction of the infected cell . The kinetics of ADCC activation are similar to those of ADCML, but efficient ADCC can already be achieved by a 10-fold lower concentration of antibodies bound to the infected cell (Perrin et al., 1977). Hence, ADCML evasion of PRV-infected monocytes by internalization of the majority of antigen-antibody complexes may not automatically imply efficient ADCC evasion. ...

Immunologic Injury in Measles Virus Infection III. Presence and Characterization of Human Cytotoxic Lymphocytes
  • Citing Article
  • February 1977

The Journal of Immunology

... For the effectiveness of the ADCML, the amount of bound antibodies is also important. The more antibodies that are bound on the surface of infected cells, the higher the percentage of lysed cells is ( Joseph et al., 1976). All FIPV-infected CrFKs showed bound antibodies on their surface. ...

Measurement of Virus Antigens on the Surfaces of HeLa Cells Persistently Infected with Wild Type and Vaccine Strains of Measles Virus by Radioimmune Assay
  • Citing Article
  • April 1976

Journal of General Virology