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Dermatology Department, Shiraz University of Medical Sciences, Shiraz, Iran
1Correspondence: P.O. Box 71955-687, Shiraz, Iran. E-mail: namazi_mr{at}yahoo.com
ABSTRACT
Activation of CD4 T cells by antigen-presenting cells is required for the full expression of most autoimmune diseases and allogeneic transplant rejection. The extracellular part of CD4 molecule is composed of four domains, D1–D4. CD4 binds to MHC class II via its D1 and D2 domains. Pyridoxal 5'-phosphate (PLP) binds very tightly to the D1 domain of CD4 and therefore could interfere with proper CD4–MHC II interaction. Nonincorporation of CD4 into the activation complex can result in T cell apoptosis and anergy to autoantigen (s). Occupancy of D1 by PLP may prevent the proper protein–protein interactions of the CD4 molecule itself, which are important in T cell activation. PLP may also interfere with the dimerization of CD4 molecules, which occurs during T cell activation, or with the interaction of this dimer with other molecules on the T cell surface, such as CD45, thereby further rendering T cells anergic or driven to apoptosis. Therefore, PLP may have utility in the treatment of autoimmunity and transplant rejection. Furthermore, as the interaction of the HIV gp120 and CD4 occurs via D1, PLP is supposed to have anti-HIV effect as well. PLP may prove of special utility in the treatment of patients affected with both autoimmunity and HIV, for whom the routine immunosuppressives are contraindicated.—Namazi, M. R. Pyridoxal 5'-phosphate as a novel weapon against autoimmunity and transplant rejection.
Key Words: autoimmunity • HIV • pyridoxal 5'-phosphate • transplant rejection • treatment • CD4
"Who is in me, heart-weary, now I know not: While I am mute, a voice within me roars ..." –Hafez Shirazi
CD4 T CELLS are integral mediators in the initiation and perpetuation of the immune responses causing autoimmune diseases and allogeneic transplant rejection (1
, 2)
.
Activation of CD4 T cells by autoantigen-MHC class II molecule assembly on the surface of antigen-presenting cells is required for the full expression of most autoimmune diseases (Fig. 1
) and for allogeneic transplant rejection, whether of the type 1 or type 2 cytokine pattern (1)
.
|
THE CD4 MOLECULE
The CD4 glycoprotein is the characteristic surface receptor of all helper T cells (3)
. In humans, monocytes/macrophages, dendritic cells, eosinophils, and reticuloendothelial cells may also express it, though at a much lower density than T helper cells. The physiological function of CD4 on non-T cells is unknown (2
, 3)
.
CD4 is a single-chain molecule with a rod-like extracellular part, a transmembrane region, and a cytoplasmic tail (Fig. 2
). The extracellular portion comprises four immunoglobulin-like domains, D1–D4 (4)
. It has been shown that CD4 binds to MHC class II via its D1 and D2 domains. Although changes in the D3 domain sometimes influence the binding, this effect is believed to be indirect by causing conformational alterations in the D1 and D2 domains (4)
. The binding appears to involve a broad area of the CD4 molecule, the D1 domain interacting with the class II ß2 domain and the D2 domain with the class II ß1 domain (Fig. 2)
. It is important that the interaction of the HIV gpl20 and the CD4 occurs via the D1 domain of the latter (4)
.
|
Therefore, CD4 provides a side of anchorage between the antigen-presenting cell and the T cell during antigen presentation and stabilizes the MHC class II/antigen/T cell receptor interaction (2)
. Moreover, the intracellular part of the CD4 molecule is associated with the protein tyrosine kinase p59lck. During antigen presentation, CD4 and the T cell receptor/CD3 complex, associated with the protein tyrosine kinase p59fyn, come into close proximity; as a result, their intracellular domains and associated protein tyrosine kinases can act synergistically in generating activation signals (2)
.
It has been estimated that complexing of CD3/CD4 increases the sensitivity of T helper cells for activation by 
100-fold (2)
. In vitro, monoclonal antibodies (mAbs) to CD4 have been shown to interfere with antigen recognition by T helper cells (2
, 3
, 5)
, to block physiological stimulation of resting T cells (2
, 5)
, and to inhibit the mixed lymphocyte reaction (2
, 6
, 7)
. In the absence of CD4-mediated, coreceptor function, ligation of the TCR by MHC–antigen complex may result in a state of antigen-specific unresponsiveness or anergy rather than activation of T cells (8)
. This is of particular interest in autoimmune disease, where it can be surmised that CD4 T cells are continuously activated by their specific autoantigen (s) presented by antigen-presenting cells expressing MHC class II molecules.
In a variety of experimental autoimmune disease in animals, mAbs to the CD4 receptor have been used successfully to prevent the induction of the disease (9
, 10)
and to induce tolerance (2
, 11)
. Of relevance to human disease, mAbs to CD4 were able to inhibit further progression when given after initial inflammation had already become manifest (2)
. For example, in mice, tolerance to human gamma-globulin could be induced when the gamma-globulin was administered together with mAbs to CD4. In contrast to mice challenged with human gamma-globulin alone, anti-CD4 mAb-treated mice failed to elicit an immune response to human gamma-globulin. These mice failed to mount an immune response upon rechallenge with human gamma-globulin without further treatment with anti-CD4 mAbs (11)
. Therefore, prevention of CD4–MHC II interaction could be used to "reprogram" the immune system (2
, 12)
.
The failure to incorporate the CD4 molecule into the activation complex can result in induction of apoptosis of the T cell (13)
.
The CD4 molecule is known to interact with CD45 on the surface of the T cell; interference with this interaction may further disrupt proper activation signals (14)
.
Though nondepleteting humanized anti-CD4 mAbs, which do not cause pan-CD4 T cell depletion, have shown favorable results in autoimmune disorders, their potential to produce high immunogenicity and vasculitic side effects has limited their clinical usage (2
, 15)
.
SPECIFIC TIGHT BINDING OF PYRIDOXAL 5'-PHOSPHATE TO CD4
The elegant studies by Salhani and co-workers have led to the discovery that PLP binds surprisingly tightly to the D1 domain of the CD4 molecule (16)
and therefore could prevent the HIV entry to CD4+ cells.
PLP blocks the anion channels of erythrocytes, platelets, parathyroid and adrenal medullary cells, and neutrophils (17)
and may interfere with the physiologic function of these cells. However, its very low affinity for anion channels permits its saturation of the CD4 receptors before significant binding to these channels takes place (18)
.
PROPOSAL
Considering that the D1 domain of CD4 plays a pivotal role in the CD4–MHC II interaction and that PLP binds tightly to this domain, and could therefore prevent D1–ß2 interaction, it could be deducted that PLP may be a useful addition to anti-autoimmunity and anti-transplant rejection armamentarium. PLP is very economical and could be administered to humans intravenously in relatively high doses (16)
.
Through failing CD4 to incorporate properly into the activation complex, PLP may induce apoptosis of T cells and tolerance to autoantigen (s).
Occupancy of D1 by PLP may prevent the proper protein–protein interactions of the CD4 molecule itself, considered important in T cell activation (18)
.
There is also evidence that CD4 molecules dimerize during T cell activation (13)
.
D1 occupancy by PLP may interfere with the dimerization process or with the interaction of this dimer with other molecules on the surface of the T cells, such as CD45. This could lead to the failure to generate activation signals, and the responding CD4 T cell may then be rendered anergic or driven to apoptosis.
PLP may prove of special value in the treatment of patients affected with both autoimmunity and HIV for whom the routine immunosuppressives are contraindicated.
ACKNOWLEDGMENTS
The author is grateful to Dr. Hendrik Schulze-Koops for providing the reprint of his invaluable article. This paper is dedicated to Prof. Karim Vessal, Editor-in-Chief of the Iranian Journal of Medical Sciences.
FOOTNOTES
Received for publication June 16, 2003. Accepted for publication August 5, 2003.
REFERENCES
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