Richard Huijbens - Academia.edu (original) (raw)

Papers by Richard Huijbens

The Journal of Immunology, 2009

Journal of Cell Science, 2001

Throughout the years, fluorescence microscopy has proven to be an extremely versatile tool for ce... more Throughout the years, fluorescence microscopy has proven to be an extremely versatile tool for cell biologists to study live cells. Its high sensitivity and non-invasiveness, together with the ever-growing spectrum of sophisticated fluorescent indicators, ensure that it will continue to have a prominent role in the future. A drawback of light microscopy is the fundamental limit of the attainable spatial

Journal of immunology (Baltimore, Md. : 1950), Jan 15, 1992

T cell-derived cytokines IFN-gamma and IL-4 have different regulatory effects on two functionally... more T cell-derived cytokines IFN-gamma and IL-4 have different regulatory effects on two functionally important molecules on human monocytes: MHC class II Ag and the Fc receptor for monomeric IgG, Fc gamma RI (CD64). MHC class II Ag, and Fc gamma RI are both upregulated in the presence of IFN-gamma. IL-4 induces MHC class II Ag expression but reduces Fc gamma RI expression. Recently, we showed that the cytokine IL-10 also affects MHC class II Ag expression. Here, we demonstrate that in contrast to the down-regulation of MHC class II Ag expression, IL-10 stimulates Fc gamma RI expression on human monocytes comparable to the levels of Fc gamma RI expression induced by IFN-gamma. The IL-10-induced Fc gamma RI expression is specific because anti-IL-10 antibodies completely reverse the IL-10-induced surface expression of Fc gamma RI and correlate with an enhanced capacity to lyse anti-D-coated human rhesus-positive erythrocytes. IL-10 fails to induce the expression of Fc gamma RII (CD32) and...

Human molecular genetics, Jan 15, 2004

With 46 subunits, human mitochondrial complex I is the largest enzyme of the oxidative phosphoryl... more With 46 subunits, human mitochondrial complex I is the largest enzyme of the oxidative phosphorylation system. We have studied the assembly of complex I in cultured human cells. This will provide essential information about the nature of complex I deficiencies and will enhance our understanding of mitochondrial disease mechanisms. We have found that 143B206 rho zero cells, not containing mitochondrial DNA, are still able to form complex I subcomplexes. To further address the nature of these subcomplexes, we depleted 143B osteosarcoma cells of complex I by inhibiting mitochondrial protein translation with doxycycline. After removing this drug, complex I formation resumes and assembly intermediates were observed by two-dimensional blue native electrophoresis. Analysis of the observed subcomplexes indicates that assembly of human complex I is a semi-sequential process in which different preassembled subcomplexes are joined to form a fully assembled complex. The membrane part of the com...

3.9)%,p b 0.05];CD4+CD8+ THY vs Tx[Tx:39.9(5.6)/SRL:23.4 (36.3)/FTY:33.4(10.2)/FTY+SRL:18.3(4.7)x... more 3.9)%,p b 0.05];CD4+CD8+ THY vs Tx[Tx:39.9(5.6)/SRL:23.4 (36.3)/FTY:33.4(10.2)/FTY+SRL:18.3(4.7)x106,p b 0.005], Ly in PB vs Tx and SRL[Tx:63.0(27.0)/SRL:50.0(14.8)/FTY:15.0 (5.0)/FTY+SRL:17.0(4.3)%,p b 0.005];CD11b+ cells in the allografts vs FTY[Tx:8.8(9.2)/SRL:7.2(6.2)/FTY:14.1(22.1)/ FTY+SRL:4.6(2.4)%,p b 0.05];higher counts of CD11b+ non-Ly in SPL vs Tx[Tx:42.9(18.2)/SRL:22.6(6.0)/FTY:21.7(5.0)/FTY+ SRL:20.7(7.1)x106,p b 0.005]; CD11b+ lymphocytes vs Tx and SRL in PB[Tx:6.0(3.5)/SRL:7.3(7.4)/FTY:50.7(3.3)/FTY+ SRL:43.5(10.6)%,p b 0.005];CD11b+ non-Ly vs Tx and SRL in PB [Tx:42.7(28.7)/SRL:56.5(42.4)/FTY:93.5(9.8)/FTY+SRL:93.4 (1.5)%,pb 0.005].Increased allograft survival in FTY+SRL was associated with decreased peripheral and allograft-infiltrating immune cells.

Monocytes activated by lipopolysaccharide (LPS) and inter- feron y (IFNy) rapidly secrete a numbe... more Monocytes activated by lipopolysaccharide (LPS) and inter- feron y (IFNy) rapidly secrete a number of monokines with different functional properties. Interleukin-4 (IL-41, a T-cell derived cytokine, has been shown to reduce the production of monokines with cytostatic activity for tumor cells, chemotactic activity for monocytes, and factors that stimu- late thymocyte proliferation. This latter activity is medi- ated by a number of monokines like IL-1, tumor necrosis factor a (TNFa), and IL-6. To elucidate which cytokines produced by monocytes are controlled by IL-4, we tested the effect of IL-4 on the secretion of IL-1 a, IL-la, TNFa, and IL-6 induced by LPS or IFNy. IL-4 was found to inhibit the secretion of IL-1s and TNFa by activated monocytes UMAN RECOMBINANT interleukin-4 (IL-4) has H pleiotropic effects.' IL-4 has been shown to act as a growth factor for activated T cells, thymocytes, natural killer cells, and B cells.2s3 IL-4 can enhance specific cytotoxic T lymphocyte (CT...

Clinical Cancer Research

The aim of this study was to evaluate the tolerability of intratumoral administered recombinant h... more The aim of this study was to evaluate the tolerability of intratumoral administered recombinant human interleukin-12 (rhIL-12) in patients with head and neck squamous cell carcinoma. Six patients were treated once a week at two dose levels of 100 or 300 ng/kg, respectively, up to 24 weeks. The primary end point was to assess the toxicity and safety of intratumoral injected rhIL-12 in head and neck squamous cell carcinoma patients; the pharmacokinetics and pharmacodynamics of rhIL-12 and any evidence of antitumor effect were also determined. Toxicity was mild, with prolonged grade 4 lymphopenia observed in only one patient. No dose-limiting toxicities occurred. In all six patients, the rhIL-12 was detectable in plasma within 30 min. Significant reductions in absolute number of peripheral blood lymphocytes and all lymphocyte subsets, especially cytotoxic T cells and natural killer cells, were observed that were maximal between 12 and 24 h. Maximal plasma concentrations of IFN-gamma an...

FEBS Journal, 2005

The oxidative phosphorylation (OXPHOS) system consists of five multiprotein complexes and two mob... more The oxidative phosphorylation (OXPHOS) system consists of five multiprotein complexes and two mobile electron carriers embedded in the lipid bilayer of the mitochondrial inner membrane. With the exception of complex II and the mobile carriers, the other parts of the OXPHOS system are under dual genetic control. Due to this bigenomic control, the inheritance of OXPHOS system defects is either maternal, in the case of mitochondrial DNA mutations, autosomal or X-linked, in the case of nuclear gene defects. In this review, our current genetic understanding of OXPHOS system enzyme deficiencies will be summarized, and future directions that the field might take to unravel so-far genetically unresolved OXPHOS system enzyme deficiencies will be described, with special emphasis on complex I biogenesis.

New England Journal of Medicine, 2014

Plasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis throu... more Plasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis through mechanisms beyond the previously suggested production of type I interferon.

The Journal of Immunology, 2009

Rheumatoid arthritis (RA) is a common autoimmune disease leading to profound disability and prema... more Rheumatoid arthritis (RA) is a common autoimmune disease leading to profound disability and premature death. Although a role for FcgammaRs and TLRs is accepted, their precise involvement remains to be elucidated. FcgammaRIIb is an inhibitory FcR important in the maintenance of tolerance. We hypothesized that the inhibitory FcgammaRIIb inhibits TLR responses on monocyte-derived dendritic cells (DC) and serves as a counterregulatory mechanism to dampen inflammation, and we surmised that this mechanism might be defective in RA. The expression of the inhibitory FcgammaRIIb was found to be significantly higher on DCs from RA patients having low RA disease activity in the absence of treatment with antirheumatic drugs. The expression of activating FcgammaRs was similarly distributed among all RA patients and healthy controls. Intriguingly, only DCs with a high expression of FcgammaRIIb were able to inhibit TLR4-mediated secretion of proinflammatory cytokines when stimulated with immune complexes. In addition, when these DCs were coincubated with the combination of a TLR4 agonist and immune complexes, a markedly inhibited T cell proliferation was apparent, regulatory T cell development was promoted, and T cells were primed to produce high levels of IL-13 compared with stimulation of the DCs with the TLR4 agonist alone. Blocking FcgammaRIIb with specific Abs fully abrogated these effects demonstrating the full dependence on the inhibitory FcgammaRIIb in the induction of these phenomena. This TLR4-FcgammaRIIb interaction was shown to dependent on the PI3K and Akt pathway.

The Journal of Immunology, 2009

TLR2 plays an important role in the removal of Gram-positive bacteria; contrastingly, it also app... more TLR2 plays an important role in the removal of Gram-positive bacteria; contrastingly, it also appears to have important protective effects against unrestrained inflammation and subsequent organ injury during infection and autoimmunity. We hypothesized that TLR2 tunes the phenotype of dendritic cells (DCs) activated through other TLRs, thereby fulfilling a crucial role in the modulation of the immune response. TLR2 potently inhibited TLR4-and TLR7/8-induced cytokine production by human DCs. The inhibitory effect of TLR2 on the release of TNF-␣ but not of IL-12p70 was mediated by PI3K. TLR2 inhibits the production of IL-12p70 by dampening the type 1 IFN amplification loop. When DCs were triggered with the potent synergistic combination of LPS (TLR4) and R848 (TLR7/8) in conjunction with a TLR2 ligand, a clear shift to more Th2-and Th17-prone responses in the naive and memory T cell subpopulations was observed. This shift in T cell responses was inherent to the inability of TLR2-stimulated DCs to produce IL-12p70 and was dependent on the production of IL-1 and IL-6.

The Journal of Immunology, 2001

Journal of Experimental Medicine, 1993

Lymphocyte function-associated antigen 1/intercellular adhesion moleculer 1 (LFA-1/ICAM-1)and ver... more Lymphocyte function-associated antigen 1/intercellular adhesion moleculer 1 (LFA-1/ICAM-1)and very late antigen 4/vascular cell adhesion molecule 1 (VLA-4/VCAM-1)-mediated adhesion of T lymphocytes to endothelial cells (EC) can be regulated by increased expression of ICAM-1 and VCAM-1 upon cytokine treatment of EC, or by activation of the integrin molecules LFA-1 and VLA-4 on T cells. Here, we provide evidence that preferential usage of LFA-1 over VLA-4 is yet another mechanism to control T cell adhesion. We observed that binding of activated T lymphocytes, as opposed to resting T cells, to EC is essentially mediated through LFA-1 and not through VLA-4. VLA-4-mediated adhesion of T cells to EC is only found when LFA-1 is not expressed or not functional, as observed for several T cell leukemia cell lines. These results suggest that LFA-l-mediated adhesion dominates and may downregulate VLA-4-mediated adhesion through an unidentified mechanism.

International Journal of Cancer, 1997

Human Molecular Genetics, 2004

With 46 subunits, human mitochondrial complex I is the largest enzyme of the oxidative phosphoryl... more With 46 subunits, human mitochondrial complex I is the largest enzyme of the oxidative phosphorylation system. We have studied the assembly of complex I in cultured human cells. This will provide essential information about the nature of complex I deficiencies and will enhance our understanding of mitochondrial disease mechanisms. We have found that 143B206 rho zero cells, not containing mitochondrial DNA, are still able to form complex I subcomplexes. To further address the nature of these subcomplexes, we depleted 143B osteosarcoma cells of complex I by inhibiting mitochondrial protein translation with doxycycline. After removing this drug, complex I formation resumes and assembly intermediates were observed by twodimensional blue native electrophoresis. Analysis of the observed subcomplexes indicates that assembly of human complex I is a semi-sequential process in which different preassembled subcomplexes are joined to form a fully assembled complex. The membrane part of the complex is formed in distinct steps. The B17 subunit is part of a subcomplex to which ND1, ND6 and PSST are subsequently added. This is bound to a hydrophilic subcomplex containing the 30 and 49 kDa subunits, to which a subcomplex including the 39 kDa subunit is incorporated, and later on the 18 and 24 kDa subunits. At a later stage more subunits, including the 15 kDa, are added and holo-complex I is formed. Our results suggest that human complex I assembly resembles that of Neurospora crassa, in which a membrane arm is formed and assembled to a preformed peripheral arm, and support ideas about modular evolution.

Clinical Immunology, 2009

3.9)%,p b 0.05];CD4+CD8+ THY vs Tx[Tx:39.9(5.6)/SRL:23.4 (36.3)/FTY:33.4(10.2)/FTY+SRL:18.3(4.7)x... more 3.9)%,p b 0.05];CD4+CD8+ THY vs Tx[Tx:39.9(5.6)/SRL:23.4 (36.3)/FTY:33.4(10.2)/FTY+SRL:18.3(4.7)x106,p b 0.005], Ly in PB vs Tx and SRL[Tx:63.0(27.0)/SRL:50.0(14.8)/FTY:15.0 (5.0)/FTY+SRL:17.0(4.3)%,p b 0.005];CD11b+ cells in the allografts vs FTY[Tx:8.8(9.2)/SRL:7.2(6.2)/FTY:14.1(22.1)/ FTY+SRL:4.6(2.4)%,p b 0.05];higher counts of CD11b+ non-Ly in SPL vs Tx[Tx:42.9(18.2)/SRL:22.6(6.0)/FTY:21.7(5.0)/FTY+ SRL:20.7(7.1)x106,p b 0.005]; CD11b+ lymphocytes vs Tx and SRL in PB[Tx:6.0(3.5)/SRL:7.3(7.4)/FTY:50.7(3.3)/FTY+ SRL:43.5(10.6)%,p b 0.005];CD11b+ non-Ly vs Tx and SRL in PB [Tx:42.7(28.7)/SRL:56.5(42.4)/FTY:93.5(9.8)/FTY+SRL:93.4 (1.5)%,pb 0.005].Increased allograft survival in FTY+SRL was associated with decreased peripheral and allograft-infiltrating immune cells.

The Journal of cell …, 1992

Investigating the regulation of very late antigen (VLA)-mediated functions, we found that TS2/16,... more Investigating the regulation of very late antigen (VLA)-mediated functions, we found that TS2/16, a mAb directed against the beta chain of the VLA group of integrins, can induce binding of resting peripheral blood lymphocytes, cloned T lymphocytes, and Epstein Barr ...

The Journal of Immunology, 2009

Journal of Cell Science, 2001

Throughout the years, fluorescence microscopy has proven to be an extremely versatile tool for ce... more Throughout the years, fluorescence microscopy has proven to be an extremely versatile tool for cell biologists to study live cells. Its high sensitivity and non-invasiveness, together with the ever-growing spectrum of sophisticated fluorescent indicators, ensure that it will continue to have a prominent role in the future. A drawback of light microscopy is the fundamental limit of the attainable spatial

Journal of immunology (Baltimore, Md. : 1950), Jan 15, 1992

T cell-derived cytokines IFN-gamma and IL-4 have different regulatory effects on two functionally... more T cell-derived cytokines IFN-gamma and IL-4 have different regulatory effects on two functionally important molecules on human monocytes: MHC class II Ag and the Fc receptor for monomeric IgG, Fc gamma RI (CD64). MHC class II Ag, and Fc gamma RI are both upregulated in the presence of IFN-gamma. IL-4 induces MHC class II Ag expression but reduces Fc gamma RI expression. Recently, we showed that the cytokine IL-10 also affects MHC class II Ag expression. Here, we demonstrate that in contrast to the down-regulation of MHC class II Ag expression, IL-10 stimulates Fc gamma RI expression on human monocytes comparable to the levels of Fc gamma RI expression induced by IFN-gamma. The IL-10-induced Fc gamma RI expression is specific because anti-IL-10 antibodies completely reverse the IL-10-induced surface expression of Fc gamma RI and correlate with an enhanced capacity to lyse anti-D-coated human rhesus-positive erythrocytes. IL-10 fails to induce the expression of Fc gamma RII (CD32) and...

Human molecular genetics, Jan 15, 2004

With 46 subunits, human mitochondrial complex I is the largest enzyme of the oxidative phosphoryl... more With 46 subunits, human mitochondrial complex I is the largest enzyme of the oxidative phosphorylation system. We have studied the assembly of complex I in cultured human cells. This will provide essential information about the nature of complex I deficiencies and will enhance our understanding of mitochondrial disease mechanisms. We have found that 143B206 rho zero cells, not containing mitochondrial DNA, are still able to form complex I subcomplexes. To further address the nature of these subcomplexes, we depleted 143B osteosarcoma cells of complex I by inhibiting mitochondrial protein translation with doxycycline. After removing this drug, complex I formation resumes and assembly intermediates were observed by two-dimensional blue native electrophoresis. Analysis of the observed subcomplexes indicates that assembly of human complex I is a semi-sequential process in which different preassembled subcomplexes are joined to form a fully assembled complex. The membrane part of the com...

3.9)%,p b 0.05];CD4+CD8+ THY vs Tx[Tx:39.9(5.6)/SRL:23.4 (36.3)/FTY:33.4(10.2)/FTY+SRL:18.3(4.7)x... more 3.9)%,p b 0.05];CD4+CD8+ THY vs Tx[Tx:39.9(5.6)/SRL:23.4 (36.3)/FTY:33.4(10.2)/FTY+SRL:18.3(4.7)x106,p b 0.005], Ly in PB vs Tx and SRL[Tx:63.0(27.0)/SRL:50.0(14.8)/FTY:15.0 (5.0)/FTY+SRL:17.0(4.3)%,p b 0.005];CD11b+ cells in the allografts vs FTY[Tx:8.8(9.2)/SRL:7.2(6.2)/FTY:14.1(22.1)/ FTY+SRL:4.6(2.4)%,p b 0.05];higher counts of CD11b+ non-Ly in SPL vs Tx[Tx:42.9(18.2)/SRL:22.6(6.0)/FTY:21.7(5.0)/FTY+ SRL:20.7(7.1)x106,p b 0.005]; CD11b+ lymphocytes vs Tx and SRL in PB[Tx:6.0(3.5)/SRL:7.3(7.4)/FTY:50.7(3.3)/FTY+ SRL:43.5(10.6)%,p b 0.005];CD11b+ non-Ly vs Tx and SRL in PB [Tx:42.7(28.7)/SRL:56.5(42.4)/FTY:93.5(9.8)/FTY+SRL:93.4 (1.5)%,pb 0.005].Increased allograft survival in FTY+SRL was associated with decreased peripheral and allograft-infiltrating immune cells.

Monocytes activated by lipopolysaccharide (LPS) and inter- feron y (IFNy) rapidly secrete a numbe... more Monocytes activated by lipopolysaccharide (LPS) and inter- feron y (IFNy) rapidly secrete a number of monokines with different functional properties. Interleukin-4 (IL-41, a T-cell derived cytokine, has been shown to reduce the production of monokines with cytostatic activity for tumor cells, chemotactic activity for monocytes, and factors that stimu- late thymocyte proliferation. This latter activity is medi- ated by a number of monokines like IL-1, tumor necrosis factor a (TNFa), and IL-6. To elucidate which cytokines produced by monocytes are controlled by IL-4, we tested the effect of IL-4 on the secretion of IL-1 a, IL-la, TNFa, and IL-6 induced by LPS or IFNy. IL-4 was found to inhibit the secretion of IL-1s and TNFa by activated monocytes UMAN RECOMBINANT interleukin-4 (IL-4) has H pleiotropic effects.' IL-4 has been shown to act as a growth factor for activated T cells, thymocytes, natural killer cells, and B cells.2s3 IL-4 can enhance specific cytotoxic T lymphocyte (CT...

Clinical Cancer Research

The aim of this study was to evaluate the tolerability of intratumoral administered recombinant h... more The aim of this study was to evaluate the tolerability of intratumoral administered recombinant human interleukin-12 (rhIL-12) in patients with head and neck squamous cell carcinoma. Six patients were treated once a week at two dose levels of 100 or 300 ng/kg, respectively, up to 24 weeks. The primary end point was to assess the toxicity and safety of intratumoral injected rhIL-12 in head and neck squamous cell carcinoma patients; the pharmacokinetics and pharmacodynamics of rhIL-12 and any evidence of antitumor effect were also determined. Toxicity was mild, with prolonged grade 4 lymphopenia observed in only one patient. No dose-limiting toxicities occurred. In all six patients, the rhIL-12 was detectable in plasma within 30 min. Significant reductions in absolute number of peripheral blood lymphocytes and all lymphocyte subsets, especially cytotoxic T cells and natural killer cells, were observed that were maximal between 12 and 24 h. Maximal plasma concentrations of IFN-gamma an...

FEBS Journal, 2005

The oxidative phosphorylation (OXPHOS) system consists of five multiprotein complexes and two mob... more The oxidative phosphorylation (OXPHOS) system consists of five multiprotein complexes and two mobile electron carriers embedded in the lipid bilayer of the mitochondrial inner membrane. With the exception of complex II and the mobile carriers, the other parts of the OXPHOS system are under dual genetic control. Due to this bigenomic control, the inheritance of OXPHOS system defects is either maternal, in the case of mitochondrial DNA mutations, autosomal or X-linked, in the case of nuclear gene defects. In this review, our current genetic understanding of OXPHOS system enzyme deficiencies will be summarized, and future directions that the field might take to unravel so-far genetically unresolved OXPHOS system enzyme deficiencies will be described, with special emphasis on complex I biogenesis.

New England Journal of Medicine, 2014

Plasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis throu... more Plasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis through mechanisms beyond the previously suggested production of type I interferon.

The Journal of Immunology, 2009

Rheumatoid arthritis (RA) is a common autoimmune disease leading to profound disability and prema... more Rheumatoid arthritis (RA) is a common autoimmune disease leading to profound disability and premature death. Although a role for FcgammaRs and TLRs is accepted, their precise involvement remains to be elucidated. FcgammaRIIb is an inhibitory FcR important in the maintenance of tolerance. We hypothesized that the inhibitory FcgammaRIIb inhibits TLR responses on monocyte-derived dendritic cells (DC) and serves as a counterregulatory mechanism to dampen inflammation, and we surmised that this mechanism might be defective in RA. The expression of the inhibitory FcgammaRIIb was found to be significantly higher on DCs from RA patients having low RA disease activity in the absence of treatment with antirheumatic drugs. The expression of activating FcgammaRs was similarly distributed among all RA patients and healthy controls. Intriguingly, only DCs with a high expression of FcgammaRIIb were able to inhibit TLR4-mediated secretion of proinflammatory cytokines when stimulated with immune complexes. In addition, when these DCs were coincubated with the combination of a TLR4 agonist and immune complexes, a markedly inhibited T cell proliferation was apparent, regulatory T cell development was promoted, and T cells were primed to produce high levels of IL-13 compared with stimulation of the DCs with the TLR4 agonist alone. Blocking FcgammaRIIb with specific Abs fully abrogated these effects demonstrating the full dependence on the inhibitory FcgammaRIIb in the induction of these phenomena. This TLR4-FcgammaRIIb interaction was shown to dependent on the PI3K and Akt pathway.

The Journal of Immunology, 2009

TLR2 plays an important role in the removal of Gram-positive bacteria; contrastingly, it also app... more TLR2 plays an important role in the removal of Gram-positive bacteria; contrastingly, it also appears to have important protective effects against unrestrained inflammation and subsequent organ injury during infection and autoimmunity. We hypothesized that TLR2 tunes the phenotype of dendritic cells (DCs) activated through other TLRs, thereby fulfilling a crucial role in the modulation of the immune response. TLR2 potently inhibited TLR4-and TLR7/8-induced cytokine production by human DCs. The inhibitory effect of TLR2 on the release of TNF-␣ but not of IL-12p70 was mediated by PI3K. TLR2 inhibits the production of IL-12p70 by dampening the type 1 IFN amplification loop. When DCs were triggered with the potent synergistic combination of LPS (TLR4) and R848 (TLR7/8) in conjunction with a TLR2 ligand, a clear shift to more Th2-and Th17-prone responses in the naive and memory T cell subpopulations was observed. This shift in T cell responses was inherent to the inability of TLR2-stimulated DCs to produce IL-12p70 and was dependent on the production of IL-1 and IL-6.

The Journal of Immunology, 2001

Journal of Experimental Medicine, 1993

Lymphocyte function-associated antigen 1/intercellular adhesion moleculer 1 (LFA-1/ICAM-1)and ver... more Lymphocyte function-associated antigen 1/intercellular adhesion moleculer 1 (LFA-1/ICAM-1)and very late antigen 4/vascular cell adhesion molecule 1 (VLA-4/VCAM-1)-mediated adhesion of T lymphocytes to endothelial cells (EC) can be regulated by increased expression of ICAM-1 and VCAM-1 upon cytokine treatment of EC, or by activation of the integrin molecules LFA-1 and VLA-4 on T cells. Here, we provide evidence that preferential usage of LFA-1 over VLA-4 is yet another mechanism to control T cell adhesion. We observed that binding of activated T lymphocytes, as opposed to resting T cells, to EC is essentially mediated through LFA-1 and not through VLA-4. VLA-4-mediated adhesion of T cells to EC is only found when LFA-1 is not expressed or not functional, as observed for several T cell leukemia cell lines. These results suggest that LFA-l-mediated adhesion dominates and may downregulate VLA-4-mediated adhesion through an unidentified mechanism.

International Journal of Cancer, 1997

Human Molecular Genetics, 2004

With 46 subunits, human mitochondrial complex I is the largest enzyme of the oxidative phosphoryl... more With 46 subunits, human mitochondrial complex I is the largest enzyme of the oxidative phosphorylation system. We have studied the assembly of complex I in cultured human cells. This will provide essential information about the nature of complex I deficiencies and will enhance our understanding of mitochondrial disease mechanisms. We have found that 143B206 rho zero cells, not containing mitochondrial DNA, are still able to form complex I subcomplexes. To further address the nature of these subcomplexes, we depleted 143B osteosarcoma cells of complex I by inhibiting mitochondrial protein translation with doxycycline. After removing this drug, complex I formation resumes and assembly intermediates were observed by twodimensional blue native electrophoresis. Analysis of the observed subcomplexes indicates that assembly of human complex I is a semi-sequential process in which different preassembled subcomplexes are joined to form a fully assembled complex. The membrane part of the complex is formed in distinct steps. The B17 subunit is part of a subcomplex to which ND1, ND6 and PSST are subsequently added. This is bound to a hydrophilic subcomplex containing the 30 and 49 kDa subunits, to which a subcomplex including the 39 kDa subunit is incorporated, and later on the 18 and 24 kDa subunits. At a later stage more subunits, including the 15 kDa, are added and holo-complex I is formed. Our results suggest that human complex I assembly resembles that of Neurospora crassa, in which a membrane arm is formed and assembled to a preformed peripheral arm, and support ideas about modular evolution.

Clinical Immunology, 2009

3.9)%,p b 0.05];CD4+CD8+ THY vs Tx[Tx:39.9(5.6)/SRL:23.4 (36.3)/FTY:33.4(10.2)/FTY+SRL:18.3(4.7)x... more 3.9)%,p b 0.05];CD4+CD8+ THY vs Tx[Tx:39.9(5.6)/SRL:23.4 (36.3)/FTY:33.4(10.2)/FTY+SRL:18.3(4.7)x106,p b 0.005], Ly in PB vs Tx and SRL[Tx:63.0(27.0)/SRL:50.0(14.8)/FTY:15.0 (5.0)/FTY+SRL:17.0(4.3)%,p b 0.005];CD11b+ cells in the allografts vs FTY[Tx:8.8(9.2)/SRL:7.2(6.2)/FTY:14.1(22.1)/ FTY+SRL:4.6(2.4)%,p b 0.05];higher counts of CD11b+ non-Ly in SPL vs Tx[Tx:42.9(18.2)/SRL:22.6(6.0)/FTY:21.7(5.0)/FTY+ SRL:20.7(7.1)x106,p b 0.005]; CD11b+ lymphocytes vs Tx and SRL in PB[Tx:6.0(3.5)/SRL:7.3(7.4)/FTY:50.7(3.3)/FTY+ SRL:43.5(10.6)%,p b 0.005];CD11b+ non-Ly vs Tx and SRL in PB [Tx:42.7(28.7)/SRL:56.5(42.4)/FTY:93.5(9.8)/FTY+SRL:93.4 (1.5)%,pb 0.005].Increased allograft survival in FTY+SRL was associated with decreased peripheral and allograft-infiltrating immune cells.

The Journal of cell …, 1992

Investigating the regulation of very late antigen (VLA)-mediated functions, we found that TS2/16,... more Investigating the regulation of very late antigen (VLA)-mediated functions, we found that TS2/16, a mAb directed against the beta chain of the VLA group of integrins, can induce binding of resting peripheral blood lymphocytes, cloned T lymphocytes, and Epstein Barr ...