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Originally published online as doi:10.1189/jlb.1103567 on February 24, 2004

Published online before print February 24, 2004
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(Journal of Leukocyte Biology. 2004;76:30-35.)
© 2004 by Society for Leukocyte Biology

Sphingosine 1-phosphate and its type 1 G protein-coupled receptor: trophic support and functional regulation of T Lymphocytes

Edward J. Goetzl1 and Markus H. Gräler

Departments of Medicine and Microbiology–Immunology, University of California, San Francisco

1Correspondence: Departments of Medicine and Microbiology–Immunology, University of California, 533 Parnassus Ave., Room UB8B, San Francisco, CA 94143-0711. E-mail: egoetzl{at}itsa.ucsf.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 IMMUNE CELL EXPRESSION, SIGNALS,...
 THE S1P AND S1P1...
 PHARMACOLOGICAL INSIGHTS FROM...
 CLINICAL IMPLICATIONS
 REFERENCES
 
The lysophospholipid (LPL) growth factors sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) are generated by macrophages, dendritic cells, mast cells, and platelets, which leads to lymph and plasma concentrations of 0.1–1 µM. Distinctive profiles of G protein-coupled receptors (GPCRs) for S1P and LPA are expressed by each type of immune cell and are regulated by cellular activation. At 1–100 nM, S1P signals T cells through their principal S1P1 GPCRs with consequent protection from apoptosis, enhancement of chemotaxis, and facilitation of optimal regulatory activity of CD4+25+ T cells. At 0.3–3 µM, S1P inhibits T cell chemotaxis and to a lesser extent other functions. These S1P–S1P1 GPCR signals suppress homing of blood and spleen T cells to secondary lymphoid tissues. S1P1 GPCR antagonists evoke lymphopenia by permitting blood T cells to enter lymph nodes and blocking S1P1 GPCR-dependent T cell efflux from lymph nodes. Inversely, there is a decrease in lymphoid tissue traffic of T cells in transgenic mice, which overexpress lymphocyte S1P1 GPCRs. The immunotherapeutic activity of S1P1 GPCR antagonists, which limits T cell access to organ grafts and autoimmune antigens, does not reduce other functional capabilities of T cells. LPLs and their GPCRs thus constitute an immunoregulatory system of sufficient prominence for pharmacological targeting in transplantation, autoimmunity, and immunodeficiency.

Key Words: lysophospholipids • immunity • chemotaxis • FTY720


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
IMMUNE CELL EXPRESSION, SIGNALS,...
 THE S1P AND S1P1...
 PHARMACOLOGICAL INSIGHTS FROM...
 CLINICAL IMPLICATIONS
 REFERENCES
 
The structurally and functionally related lysophospholipid (LPL) growth factors sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) are generated from lipid stores by cellular enzymatic pathways, secreted, bound by proteins of plasma and lymph, and degraded by distinctive phosphatases and lipases [1 2 3 4 ]. In the immune system, macrophages, dendritic cells, mast cells, and platelets are the principal sources of S1P and LPA (Fig. 1 ). S1P and LPA are separately recognized by distinct subsets of a family of G protein-coupled receptors (GPCRs), respectively designated S1P1–5 and LPA1–4 [5 ]. Each type of immune cell so far examined has a different profile of expression of S1P and LPA GPCRs (Fig. 1) . Human and mouse T cells have predominately S1P1, S1P4, and LPA2, and CD8 but not CD4 T cells also bear S1P5 [6 7 8 9 10 ]. Each type of S1P and LPA GPCR is coupled to a different set of signaling pathways and is down-regulated by T cell activation through diverse pathways, which represents the principal mechanism for control of LPL effects on T cells. The S1P and LPA GPCRs are refractory to chronic ligand-induced down-regulation and thus maintain persistent transductional activity in blood and lymph T cells despite complete occupancy with ligand.



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  		Figure 1. Immune cellular generation and recognition of S1P and LPA. NK, Natural killer.

 
S1P is far more effective than LPA as a regulator of major T cell functions, and most of these activities are transduced by S1P1 GPCRs [10 , 11 ]. The influences of LPLs on cellular functions have been considered in two categories, one of which is growth-related and includes stimulation of proliferation and suppression of apoptosis, and the other is cytoskeleton-based and encompasses elicitation of adhesion, contraction, movement, and secretion. For T cells, the equivalent categories are first, alteration of proliferation and suppression of apoptosis and second, effects on chemotaxis, cytokine generation, and specialized activities such as cytotoxicity and regulatory functions. Which effect will predominate is determined by LPL concentration, GPCR density, and the array of coupled G proteins in the host cell. Some of the recent excitement in this field also is attributable to the strong possibility of discovering unique classes of immunoactive drugs that target S1P GPCRs selectively. Newly established mouse genetic models of altered expression of T cell S1P GPCRs and novel, functional anti-S1P GPCR monoclonal antibodies (mAb) now have provided systems and reagents for analyzing further the separate immune contributions of each of the predominant T cell S1P GPCRs. The results of such studies also may permit accurate predictions of the immune effects of individual S1P GPCR-selective agonists and antagonists.


   IMMUNE CELL EXPRESSION, SIGNALS, AND FUNCTIONAL EFFECTS OF LPA AND S1P GPCRs
TOP
 ABSTRACT
 INTRODUCTION
 IMMUNE CELL EXPRESSION, SIGNALS,...
THE S1P AND S1P1...
 PHARMACOLOGICAL INSIGHTS FROM...
 CLINICAL IMPLICATIONS
 REFERENCES
 
The earliest analyses of lymphocyte LPA and S1P GPCRs, by polymerase chain reaction (PCR) and Western blot techniques, showed that lines of human T cell tumors express similar levels of LPA1, LPA2, S1P2, and S1P3 GPCRs without significant alterations in these levels by numerous, different stimuli [12 ]. In contrast, human blood and mouse spleen CD4 T cells and B cells express predominately S1P1, S1P4, and LPA2 GPCRs, as assessed by the same methods (Fig. 1) [7 , 9 ]. Mouse and human spleen CD8 T cells express the same three major LPA and S1P GPCRs as CD4 T cells but also express S1P5. Activation of each of these sets of normal lymphocytes with a preferred stimulus transcriptionally down-regulates the S1P1, S1P4, and LPA2 GPCRs and concurrently up-regulates LPA1 GPCRs [7 , 9 ]. The down-regulation of LPA and S1P GPCRs contrasts with up-regulation of chemokine GPCRs, observed after similar stimulation of T cells. S1P1 and S1P4 GPCR down-regulation in mouse CD4 T cells was sufficient to suppress an array of biochemical and functional responses to S1P, which could be largely reconstituted by introduction of recombinant S1P1 but not S1P4 GPCRs [11 ]. The mechanisms of principal expression of LPA1, S1P1, and S1P2 by macrophages and other mononuclear phagocytes, S1P1, S1P2, S1P3, and S1P4 by diverse dendritic cells, and S1P1, S1P4, and S1P5 by NK cells (Fig. 1) and the optimal conditions for respective coupling of S1P GPCRs to immune activities of these other types of cells have only recently been examined.

Profiles of T cell LPA GPCRs (Rs), based initially on radioactive, semiquantitative PCR and Western blots, showed that human unactivated CD4 T cells and CD8 T cells from blood expressed predominately LPA2 Rs, a level of LPA1 Rs less than 10% that of LPA2 Rs, and no detectable LPA3 Rs. The levels of mRNA encoding LPA1–3 Rs were requantified subsequently by TaqMan real-time PCR, which confirmed the original results for human blood T cells and demonstrated the same levels for mouse spleen CD4 and CD8 T cells. The level of LPA2 Rs decreased 30–50%, and the level of LPA1 Rs increased to a mean of 50–100% that of the LPA2 Rs after activation by mitogen or adherent anti-CD3 plus anti-CD28 mAb [7 ]. The functional difference between isolated expression of LPA2 Rs in unactivated CD4 T cells and codominant expression of LPA2 Rs and LPA1 Rs in activated CD4 T cells was examined through interleukin (IL)-2 generation. Acute induction of IL-2 secretion from naïve, unactivated human blood or mouse spleen CD4 T cells over 24 h by anti-CD3 plus anti-CD28 mAb was suppressed up to 60% by 10–10 M–10–6 M LPA and anti-LPA2 R mouse mAb [7 ]. When LPA2 Rs were reduced and LPA1 Rs up-regulated by preactivation of CD4 T cells, IL-2 secretion evoked by anti-CD3 plus anti-CD28 mAb stimulation was enhanced up to twofold by 10–10 M–10–6 M LPA and by anti-LPA1 R mAb [7 ]. Similarly, the two major LPA Rs of CD4 T cells transduced opposite effects on chemotaxis in Transwell chambers with Matrigel-coated, 5-µm pore filters with LPA2 R elicitation and LPA1 R inhibition of chemotaxis [7 ]. The inhibitory effect of LPA1 Rs was confirmed in a Jurkat human T cell-transfected LPA1 R model [8 ]. Jurkat–T–LPA1 R cells did not respond directly to LPA or anti-LPA1 R mAb, but chemokine-evoked chemotaxis was normal and was inhibited by 10–8 M–10–6 M LPA and anti-LPA1 R mAb [8 ].

Systematic studies of T cell S1P GPCRs were initiated when preliminary results suggested that these were more important than LPA Rs in regulating several aspects of T cell movements required for thymic egress, lymphoid tissue distribution, and diverse responses to complex antigenic challenges. The quantitatively predominant S1P Rs of T cells are S1P1 and S1P4, as assessed by TaqMan real-time PCR and Western blots, and the former appears to transduce most functional signals from S1P to T cells. In contrast to LPA Rs, S1P1 and S1P4 are down-regulated by all T cell stimuli that have been examined, including many mitogens, anti-CD3 plus anti-CD28 mAb, superantigens, and phorbol esters [9 ]. CD4 T cell levels of S1P1 and S1P4 are higher than those of CD8 T cells and B cells, but the basic profiles are similar. The major effects of S1P on T cell functions are highly S1P concentration-dependent (Table 1 ) [9 , 10 ]. At levels of 1–100 nM, which are found in tissues, S1P exerts principally supportive, permissive, and stimulatory effects on T cells (Table 1) . In this range, S1P evokes direct chemotaxis and enhances chemotaxis to chemokines optimally. At these same concentrations, S1P also suppresses apoptosis, permits optimal suppression of effector T cell activities by CD4+25+ Treg cells, and supports full activity of cytotoxic T cells. In contrast, blood and lymph concentrations of 0.3–3.0 µM S1P are uniformly inhibitory of T cell functions (Table 1) . In this range of concentrations, S1P inhibits chemokine-elicited chemotaxis by up to 90% [10 ]. In the context of a vast array of known lymphocyte chemotactic factors, the capacity of S1P but not LPA to inhibit chemotactic responses of naïve and possibly memory T cells to chemokines is a most unique and quantitatively striking effect. The chemotactic inhibitory activity of blood and lymph concentrations of S1P is one basis for a new, conceptual model of the T cell regulatory activities of S1P and explains the mechanism of action of an immunosuppressive drug designated 2-amino-2[2-(4-octylphenyl)ethyl]-propane-1,3-diol hydrochloride (FTY720) [13 , 14 ], which also acts on many S1P GPCRs.


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  		Table 1. Two Different Sets of T Cell Activities of the S1P–S1P1 GPCR Axis

 
In contrast to the LPA GPCRs, which act solely on T cell production of IL-2, the S1P GPCRs have no effect on IL-2 production but instead suppress generation of specialized functional cytokines, such as interferon-{gamma} (IFN-{gamma}) and IL-4 and proliferation of T cells (Table 1) [11 ]. Proliferation of mouse spleen CD4 T cells, assessed by uptake of 3H-thymidine and cell counts, was suppressed by 10–9 M–10–6 M S1P, with mean maximal suppression at the highest concentration of 48–50% when the stimuli were anti-CD3 mAb plus anti-CD28 mAb or IL-7. In contrast, 10–6 M LPA only suppressed proliferation by a mean of 16% (P<0.05) when the stimulus was anti-CD3 plus anti-CD28 mAb and had no effect when CD4 T cells were activated by anti-CD3 mAb plus IL-7 [11 ]. An increase in [Ca++]i is an obligatory event in the pathway by which S1P suppresses CD4 T cell proliferation. Similar results were obtained with CD8 T cells. Studies then were extended to cytokine generation by activated CD4 T cells. Mean maximal inhibition of IL-2 secretion by 10–8 M–10–6 M LPA exceeded 50%, but 10–10 M–10–6 M S1P had no effect on IL-2 secretion [7 , 11 ]. Although levels of secretion of IL-4 and IFN-{gamma} were much lower after 6–24 h than at 72 h, partial persistence of the S1P Rs during the 24 h after stimulation permitted modulation by S1P. In contrast to the profile for IL-2, 10–8 M–10–6 M S1P, but not LPA, suppressed secretion of IFN-{gamma} by stimulated CD4 cells up to 70%. S1P inhibition of IL-4 secretion by CD4 T cells depended on the stimulus. With anti-CD3 mAb plus IL-7, T cell secretion of IL-4 was suppressed significantly and progressively by 10–8 M–10–6 M S1P, but with anti-CD3 plus anti-CD28 mAb, inhibition was only significant at 10–6 M S1P [11 ]. Only IL-4 secretion elicited by the former stimulus was slightly suppressed by LPA and only at 10–6 M.

Although some aspects of the T cell immunoregulatory signals from S1P and LPA GPCRs have been elucidated, many critical questions remain unanswered or only partially answered. Certain specialized and very distinctive cellular mechanisms controlling down-regulation and re-expression of T cell S1P GPCRs have been identified recently in vitro, but most of the protein phosphorylation events remain to be delineated at the molecular level [15 ]. Further, the individual contributions of each T cell LPA and S1P GPCR to transduction of the respective net effects of LPA and S1P on T cell functions also have been only partially delineated in vitro. Little is known about regulation of expression or functional effects of any T cell S1P or LPA GPCR in vivo during immune responses. Nonetheless, the weight of present evidence favors a dominant role for T cell S1P1 GPCRs in S1P control of migration and specific functions of T cells [9 , 11 ].


   THE S1P AND S1P1 GPCR IMMUNOREGULATORY AXIS: CONTROL OF T CELL MIGRATION
TOP
 ABSTRACT
 INTRODUCTION
 IMMUNE CELL EXPRESSION, SIGNALS,...
 THE S1P AND S1P1...
PHARMACOLOGICAL INSIGHTS FROM...
 CLINICAL IMPLICATIONS
 REFERENCES
 
That S1P1 GPCRs are the principal transducers of S1P effects on T cell migration was suggested initially by findings that prior activation of T cells sufficient to nearly completely down-regulate S1P1 Rs and S1P4 Rs ablated functional responses to S1P and that selective reintroduction of S1P1 but not S1P4 restored such T cell responses to S1P [9 , 11 ]. Further support for the hypothesis came from the observation that S1P-induced migration of S1P R null hepatoma cells transfected with S1P1 Rs but not S1P4 Rs. Confirmation also came from limited applications of functional mAb and S1P R-selective antagonists, where those specific for S1P1 Rs but not those directed to S1P4 Rs suppressed chemotactic and chemotactic-inhibitory effects of S1P in vitro and in vivo. The first definitive set of studies of T cells used a line of T helper type 1 (Th1) cells, generated by cytokine-directed deviation of splenic CD4 T cells of D011.10 ovalbumin (OVA) peptide-specific T cell receptor (TCR) transgenic mice, in which the expression of S1P1 Rs and S1P4 Rs was suppressed more than 90% by pulses of stimulation with OVA peptide antigen and antigen-presenting cells every 5–6 days. In these functionally S1P GPCR null Th1 cells, retrovirally mediated introduction of human S1P1 Rs led to far greater, direct chemotactic responses to S1P, S1P inhibition of CCL-5-induced chemotaxis, and S1P inhibition of anti-TCR mAb-evoked proliferation and cytokine production than in sham S1P1 R transductants or S1P4 R transductants [11 ]. These results all implicated S1P1 GPCRs as the major T cell transducers of signals from S1P and supported multifunctional, immunoregulatory roles for the S1P–S1P1 GPCR axis (Fig. 1) .


   PHARMACOLOGICAL INSIGHTS FROM THE S1P GPCR ANTAGONIST FTY720
TOP
 ABSTRACT
 INTRODUCTION
 IMMUNE CELL EXPRESSION, SIGNALS,...
 THE S1P AND S1P1...
 PHARMACOLOGICAL INSIGHTS FROM...
CLINICAL IMPLICATIONS
 REFERENCES
 
An immunosuppressive compound termed ISP-1 or Myriocin was isolated from the ascomycete Isaria sinclairii, which was long used as an "eternal youth" nostrum in China [13 ]. Substantial and limiting gastrointestinal side-effects of Myriocin led to a series of chemical modifications. The most active derivative was FTY720, which is immunosuppressive in numerous T cell-dependent assays [14 ]. Intravenous or oral FTY720 induced profound lymphopenia and suppressed the levels of recirculating lymphocytes in lymphatics of mice within hours by shifting the lymphocyte contents of blood and spleen to secondary lymphoid organs [16 , 17 ]. Egress of lymphocytes from lymph nodes also was inhibited by FTY720. The major immune-functional consequence of lymphocyte redistribution by FTY720 was immunosuppression in rodent models of transplantation and autoimmune diseases. Application of FTY720 in human renal transplantation, usually with coadministration of low-dose cyclosporine, afforded excellent protection from rejection without increasing the risk of infections [18 ]. A phosphorylated form of FTY720 subsequently was found to be an agonist for S1P GPCRs and was postulated to be the mediator of FTY720-immunosuppressive effects [16 , 17 ], but the specific mechanisms of action have not been fully elucidated and are a source of current controversy.

The first hypothesis is that FTY720 is phosphorylated, primarily by sphingosine kinases and perhaps other principally intracellular kinases. FTY720 phosphate then acts as an agonist for several lymphocyte S1P GPCRs to stimulate movement of blood and spleen lymphocytes into lymph nodes and maintain their intranodal sequestration, presumably by inducing a state of unresponsiveness to S1P or other chemotactic factors [16 , 17 ]. These effects require micromolar concentrations of FTY720 for optimal phosphorylation and lymphocyte stimulation in vitro. The most convincing supporting data for this first possibility are from in vivo studies, but few analyses of cellular mechanisms of action of FTY720 phosphate have been conducted with lymphocytes in vitro. The second hypothesis is that unaltered FTY720 acts at the nanomolar concentrations attained in patients on treatment to inhibit lymphocyte S1P1 GPCRs selectively, without any agonist or direct antagonist activity. FTY720 has been shown recently to induce internalization and consequently loss of signaling activity of S1P1 GPCRs but not S1P4 GPCRs. By the second hypothesis, FTY720 is designated a noncompetitive inhibitor of S1P1, S1P2, and S1P5 but not S1P3 or S1P4 GPCRs, based on results of studies in a series of model cell transductants and of S1P1 GPCRs alone in lymphocytes. FTY720 thereby suppresses S1P inhibition of lymphocyte chemotaxis to lymph node chemokines and thus accelerates lymphocyte migration from blood and spleen into lymph nodes (Fig. 2a and 2b ). Concurrently, FTY720 also blocks the lymph node lymphocyte chemotactic response to S1P required for their return into lymph and then blood (Fig. 2c) . Many aspects of the FTY720 effects on S1P regulation of lymphocyte traffic, which account for its highly selective and relatively safe immunosuppressive profile, have not been fully delineated. Further, it is also likely that the mechanisms of the second hypothesis are exercised with cellular selectivity, as there is evidence against their applicability to some endothelial cell responses to FTY720. The relative contributions of different mechanisms of action of FTY720 thus may depend on the type of target cell. In addition, it remains to be established how TCR stimulation down-regulates S1P GPCRs and what natural factors in lymph down-regulate S1P1 Rs of the majority of T cells in HEVs, which do not have activating interactions with antigen or exposure to a drug such as FTY720 in the course of normal trafficking. Finally, investigations of the ability of FTY720 to influence activated effector T cells, which have much lower levels of S1P Rs than naïve and memory cells, have yielded conflicting results depending on their source, and more studies will be required.



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  		Figure 2. S1P–S1P1 GPCR axis regulation of T cell traffic in primary and secondary immune organs. The solid arrows from spleen to blood and from blood to secondary lymphoid organs depict T cell movement and the inhibitory trapping of the S1P–S1P1 R axis. The dashed arrows (a and b) show facilitation of T cell chemotaxis by FTY720, and the serpentine arrow (c) shows FTY720 inhibition of chemotactic responses to S1P. HEV, High endothelial venule.

 

   CLINICAL IMPLICATIONS
TOP
 ABSTRACT
 INTRODUCTION
 IMMUNE CELL EXPRESSION, SIGNALS,...
 THE S1P AND S1P1...
 PHARMACOLOGICAL INSIGHTS FROM...
 CLINICAL IMPLICATIONS
REFERENCES
 
The capacity of antagonists and agonists of the S1P1 GPCR–S1P axis to modify tissue distribution and effector chemotactic responses of T cells, without substantially altering their intrinsic, immune activities, represents a novel and potentially safer approach to immunotherapy in transplantation rejection and autoimmunity. The multi-S1P GPCR-directed agent FTY720, which acts as a noncompetitive inhibitor at nanomolar concentrations and an agonist after phosphorylation, suppresses immune rejection of transplanted organs and a wide range of different forms of autoimmunity in animal models of multiple sclerosis, rheumatoid arthritis, type 1 diabetes mellitus, and other organ-specific reactions [19 20 21 22 ]. FTY720 also has been beneficial for treatment of human renal graft rejection, especially in combination with low-dose cyclosporine. All of these successful applications of FTY720 in immunoregulation have been in conditions where T cell involvement is a critical requirement. The predicted lack of susceptibility to infections in FTY720 recipients also has held true. Preliminary results of studies of several nonlipid, small organic compounds with S1P1 GPCR-selective antagonistic activity also have shown immunoregulatory effects similar to those of FTY720. Early characterization of lymphocyte-targeted S1P1 transgenic mice and conditional, S1P1 null mice reveals phenotypes with major immune abnormalities, which center on lymphocyte migration and tissue distribution.

Numerous lines of evidence support a necessary role for S1P in T cell recruitment and effector activation. However, these data do not all convincingly implicate S1P1 GPCRs as the sole transducer of S1P signals, and some data suggest possible contributions of S1P4 GPCRs and of LPA GPCRs. Involvement of the S1P GPCR–S1P systems in functions of other immune cells is less well-defined, and implications for human biology and diseases are consequently less clear. Mononuclear phagocytes express a profile of LPA and S1P GPCRs distinct from that of lymphocytes and demonstrate migration and cytokine responses, but differences among monocytes and tissue-specific sets of macrophages also remain to be elucidated. Developing and mature dendritic cells express not only the predominant S1P1 and S1P4 GPCRs of lymphocytes but similar levels of S1P2 and S1P3 as well. Currently, available data do not permit assignment of any of the S1P-evoked migratory or cytokine responses of dendritic cells to individual S1P GPCRs. Although it is currently impossible to accurately predict how S1P GPCR-selective agonists or antagonists will affect dendritic cell recruitment and activation, one or more such agents alone or in combination with other immunostimulants are expected to enhance dendritic cell mobilization and differentially alter their capacity to induce Th1 and Th2 responses to vaccines.

Future research designed to elucidate functions of LPLs and their GPCRs in natural immunity and in immune-therapeutic applications should proceed with the knowledge of elements which distinguish these systems from all immune cytokines and mediators described previously. Many of the regulatory roles of LPLs and their GPCRs in normal immunity result from constitutive signaling of lymphocytes and other immune cells by S1P1 and perhaps other S1P GPCRs, which are fully occupied at usual plasma and lymph concentrations of S1P. Effects of these systems during active, immune responses are almost solely mediated by changes in the levels of expression of S1P GPCRs by lymphocytes and other immune cells. Although fluid concentrations of S1P and LPA also may change in these responses, such alterations in ligands have relatively little influence on immunity. All major immunoregulatory activities of LPLs and their GPCRs are attributable directly or indirectly to effects on immune cell responses to antigens, cytokines, or other immune mediators. Thus, these systems and agents that act on them should be characterized in their immune context and to the extent possible with complete knowledge of other relevant immune factors.


   ACKNOWLEDGEMENTS
 
Grant HL31809 from the National Institutes of Health supported this work.

Received November 14, 2003; accepted December 30, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 IMMUNE CELL EXPRESSION, SIGNALS,...
 THE S1P AND S1P1...
 PHARMACOLOGICAL INSIGHTS FROM...
 CLINICAL IMPLICATIONS
 REFERENCES
 

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