Analysis of human cytomegalovirus (HCMV) primary infection in immunocompetent (n=40) and immunocompromised transplant patients (n=20) revealed that the median peak antibody titre neutralizing infection of epithelial cells was 16-fold higher in immunocompromised patients. The mechanism of this finding was investigated by measuring: (i) HCMV DNAemia; (ii) HCMV neutralizing antibodies; (iii) ELISA IgG antibody titre to HCMV glycoprotein complexes gHgLpUL128L, gHgLgO and gB; and (iv) HCMV-specific (IFN-gamma(+)) CD4(+) and CD8(+) T-cells. Circulating CXCR5(+) CD4+ (memory T follicular helper - T-FH-cells) were identified as activated TFH (ICOS+PD-1(++)CCR7(lo)) and quiescent cells. In the early stages of primary infection, activated TFH cells increased in number. Concomitantly, both neutralizing and IgG antibodies to HCMV glycoproteins reached a peak, followed by a plateau. A stop in antibody rise occurred upon appearance of HCMV-specific CD4(+) T-cells, HCMV clearance and progressive reduction in activated TFH cells. The main differences between healthy and transplant patients were that the latter had a delayed DNA peak, a much higher DNA load and delayed activated TFH cells and antibody peaks. Similar events were observed in clinically severe HCMV reactivations of transplant patients. A preliminary analysis of the specificity of the activated TFH cell response to viral proteins showed a major response to the pentamer gHgLpUL128L and gB. In conclusion, in the absence of T-cell immunity, one of the first lines of defence, during primary infection, is conferred by antibodies produced through the interaction of TFH cells and B-cells of germinal centres, resulting in differentiation of B-cells into antibody producing plasma cells.

Follicular helper T-cells and virus-specific antibody response in primary and reactivated human cytomegalovirus infections of the immunocompetent and immunocompromised transplant patients

Carrara, E.;
2016

Abstract

Analysis of human cytomegalovirus (HCMV) primary infection in immunocompetent (n=40) and immunocompromised transplant patients (n=20) revealed that the median peak antibody titre neutralizing infection of epithelial cells was 16-fold higher in immunocompromised patients. The mechanism of this finding was investigated by measuring: (i) HCMV DNAemia; (ii) HCMV neutralizing antibodies; (iii) ELISA IgG antibody titre to HCMV glycoprotein complexes gHgLpUL128L, gHgLgO and gB; and (iv) HCMV-specific (IFN-gamma(+)) CD4(+) and CD8(+) T-cells. Circulating CXCR5(+) CD4+ (memory T follicular helper - T-FH-cells) were identified as activated TFH (ICOS+PD-1(++)CCR7(lo)) and quiescent cells. In the early stages of primary infection, activated TFH cells increased in number. Concomitantly, both neutralizing and IgG antibodies to HCMV glycoproteins reached a peak, followed by a plateau. A stop in antibody rise occurred upon appearance of HCMV-specific CD4(+) T-cells, HCMV clearance and progressive reduction in activated TFH cells. The main differences between healthy and transplant patients were that the latter had a delayed DNA peak, a much higher DNA load and delayed activated TFH cells and antibody peaks. Similar events were observed in clinically severe HCMV reactivations of transplant patients. A preliminary analysis of the specificity of the activated TFH cell response to viral proteins showed a major response to the pentamer gHgLpUL128L and gB. In conclusion, in the absence of T-cell immunity, one of the first lines of defence, during primary infection, is conferred by antibodies produced through the interaction of TFH cells and B-cells of germinal centres, resulting in differentiation of B-cells into antibody producing plasma cells.
Antibodies, Neutralizing
Antibodies, Viral
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Cytomegalovirus
Cytomegalovirus Infections
DNA, Viral
Enzyme-Linked Immunosorbent Assay
Germinal Center
Humans
Immunocompromised Host
Immunoglobulin G
Neutralization Tests
T-Lymphocytes, Helper-Inducer
Viral Load
Viremia
Antibody Formation
Transplant Recipients
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11562/1071248
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