macrophages, suggesting that the t cells are presented with myelin lipids by cd1 molecules at sites of inflammation. hemostasis/thrombosis sulfatide has roles in both blood coagulation and anticoagulation. sulfatide has anticoagulation activity when it binds to fibrinogen, which prevents fibrinogen from converting to fibrin. sulfatide also has a direct inhibitory effect on thrombosis. on the other hand, sulfatide also helps to improve blood coagulation and thrombosis: first, sulfatide is believed to aid in thrombosis through its participation with coagulation factor xii; second, sulfatide binding to annexin v accelerates coagulation; third, sulfatide and p-selectin interactions expressed on platelets, help to ensure stable platelet adhesion and aggregation. however, most of these conclusions have been drawn using exogenous forms of sulfatide. consequently, additional research and experimentation on endogenous sulfatide is necessary to fully understand the role of sulfatide in coagulation and thrombosis. sulfatide is also present in serum lipoproteins, which are believed to be associated with the cause and development of cardiovascular disease. kidney sulfatide can also be found in the kidney. although sulfatide is not necessary for the kidneys to maintain their function and structure, it does play an active role in different aspects of the kidney. for example, sulfatide is a ligand for l-selectin, which is a receptor that can be found in the kidneys. specifically, l-selectin is a lymphoid receptor, and the binding between l-selectin and sulfatide in the kidney's interstitium plays a major role in monocyte permeation and infiltration into the kidney. additionally, sulfatide is also found in the glandular stomach epithelium and in the apical membranes of the distal kidney tubuli where myelin and lymphocyte protein (mal) is expressed. mal forms complexes with sulfatide and other glycosphingolipids, and these complexes have been shown to play a role in apical sorting and stabilization of sphingoglycolipid enriched areas. role in pathological cells and tissue sulfatide has been shown to play a role or have some association with several diseases and infections. this includes diabetes mellitus, cancer and tumors, metachromatic leukodystrophy, various bacterial infections, and viruses, including hiv-1, hepatitis c, influenza a virus, and vaccinia virus. metachromatic leukodystrophy arylsulfatase a metachromatic leukodystrophy, also known as mld, is a recessive lysosomal storage disorder. it is believed to be caused by a deficiency in arylsulfatase a. arylsulfatase a is a lysosomal sulfatase that is able to hydrolyze the 3-o-sulfogalactosylceramide and 3-o-sulfolactosylceramide. both 3-o-sulfolactosylceramide and 3-o-sulfogalactosylceramide can be located mainly in the central nervous system as well as in the peripheral nervous system. when lacking the lysosomal enzyme or mutations in the gene coding for saposin b occur, this can lead to the accumulation of lysosomal sulfatide, which then develops into metachromatic leukodystrophy. sulfatide plays an important role in the myelin. myelin acts as an insulating sheath that surrounds many nerve fibers and increases the speed at which impulses are conducted. when sulfatide is not distributed properly, it can affect the normal physiological conduction of electrical impulses between nerve cells. this then results in demyelination because of the buildup of sulfatide and is the main cause of metachromatic leukodystrophy. however, how sulfatide buildup causes demyelination and neural degeneration is still mostly unknown. metachromatic leukodystrophy results in neurological manifestations that are centered on the impairment of the central nervous system and the peripheral nervous system, including the following: seizures, progressive coordination and speech problems, and behavioral disturbances. treatment is still being studied and evaluated, but mice studies indicate that treatments, including gene therapy, cell-based therapies using oligodendrocyte progenitors cells, enzyme replacement therapy, or adeno-associated viral and lentiviral mediated gene therapy may prove to be effective in reducing the effects of metachromatic leukodystrophy. diabetes mellitus sulfatide has several isoforms, including c16:0, which is found primarily in the secretory granules and toward the surface of the membrane of β cells. secretory granules and β cells are found in the islet of langerhans and in rat β tc3 cells. research has shown that in the pancreases of type ii diabetic mouse models, there is a deficiency of c16:0. additional research has shown that c16:0 plays an important role in assisting to improve insulin crystal preservation, and as the β cells in the pancreas secrete insulin, sulfatide aids in the monomerization of insulin, which is the breakdown of insulin into its basics components or monomers. consequently, sulfatide is needed in order to maintain normal insulin secretion, which sulfatide is capable of mediating through stimulation of calcium dependent exocytosis and adenosine triphosphate (atp)-sensitive potassium ion channels. sulfatide can also stimulate proinsulin folding as well, as it can serve as a molecular chaperone for insulin. in the diagnosis of type i diabetes, elevated anti-sulfatide antibodies in serum arise. such anti-sulfatide antibodies prevent insulin secretion and exocytosis. however, research has shown that when non-obese diabetic mice are treated with sulfatide, it reduces the possible occurrence of diabetes from 85% in control animals to 35% in experimental animals. sulfatide is also commonly known to possess anti-inflammatory properties. as a result of these anti-inflammatory properties, which aid in the blockage of l-selectin, sulfatide has been shown to prevent type i diabetes and inhibit insulitis in non-obese diabetic mice. sulfatide also prevents apoptosis in insulin secreting cells by preventing the effects of interleukin-1 beta (ll-1β), interferon beta 1b (lfn-1β), and tumor necrosis factor alpha (tnf-α) that promote apoptosis. sulfatide may also be involved in not just type i diabetes, but also type ii diabetes. specifically, sulfatide is capable of inhibiting tnf-α secretion. when there are low serum levels of sulfatide, as well as elevated production of tnf-α in patients that have type ii diabetes, it is commonly associated with insulin resistance. however, sulfatide may mediate suppression of type ii diabetes through the activation of potassium protein channels. cancer and tumor elevated sulfatide is common in many tissues in the human body, including numerous cancer tissues and cells. these include: primary lung adenocarcinoma primary colorectal cancer tissues primary lung adenocarcinoma tissues malignant and benign ovarian cancer tissues renal carcinoma tissues serous papillary ovarian carcinoma tissues gastric cancer tissues renal carcinoma (smkt-r3 cell line) sulfatide levels in these cancer lines and tissues may vary. for example, the levels of sulfatide are much lower in undifferentiated small cell carcinoma tissues and primary lung squamous cell carcinoma tissues in humans than in primary lung adenocarcinoma tissue in humans. in human ovarian cancers, sulfatide levels are much higher in malignant ovarian cancers than in benign ovarian cancers. other cancers such as wilms’ tumor show no expression of sulfatide. therefore, it appears that such increased levels of sulfatide are not universal in every form of cancer, and more experimentation must be done to confirm that elevated levels of sulfatide are not just artifacts of cultured cancer cell lines. p-selectin however, experimentation using renal cancer cell lines has given some insight into the mechanism for the elevated levels of sulfatide expression in cancer cells. specifically, cerebroside sulfotransferase (cst) is elevated as it passes along a signaling pathway which involves: hepatocyte growth factor epidermal growth factor tyrosine kinases tnf-α protein kinase c ras this path results in the accumulation of sulfatide in renal cancer cell lines. additionally, sulfatide can accumulate on the surface of cancer cells. this indicates that sulfatide may serve as a specific ligand for p-selectin. this would contribute to increased metastasis of the cancer. however, more research is needed to elucidate the relationship between the elevated levels of sulfatide expression and the initiation and metastasis mechanisms of cancer, but sulfatide may be a useful serum biomarker for early tumor detection. viral infection experimentation with sulfatide has shown that it has involvement in several viral infections, including hiv-1, influenza a virus, hepatitis c, and the vaccinia virus. hiv-1 v3 loop fragment of the hiv-1 envelope gp120 complex sulfatide shows involvement in hiv-1 infection. gp120-gp41 are specific types of envelope glycoprotein complexes that are found on hiv-1. these glycoprotein complexes can interact with cd4, a viral receptor molecule, which induces a change in the conformation of gp120. this change in conformation allows the gp120 complex to interact with the chemokine co-receptor and the insertion of the fusion peptide, gp41, into the membrane of the host cell. this allows the hiv-1 virus to enter into the cell. gp120 can also bind to glycolipids like sulfatide and galactocerebroside (galcer). sulfatide binds strongly to the v3 loop of gp120, which does not interact with cd4. consequently, sulfatide acts as an alternate virus receptor in cd4- cells, and it participates in transmembrane signaling. however, sulfatide has little function in hiv-1 infection of cd4+ cells. the binding of gp120 to galcer has the ability to start the fusion of hiv-1, but the binding of gp120 to sulfatide does not. sulfatide is not a functional receptor. however, experiments have shown that sulfatide and galcer compete for the ability to bind to gp120, and sulfatide has been shown to have the strongest binding affinity for recombinant gp120 of all the glycolipids tested. therefore, this suggests that when sulfatide is attached to hiv-1, it cannot interact with the chemokine co-receptor because of the instability of the complex between gp120 and sulfatide, which therefore prevents the initiation of the fusion process. this indicates that sulfatide can prevent hiv-1 infection by mediating gp120 binding, which, in turn, prevents the fusion process; consequently, it has been demonstrated that sulfatide treatments may lead to the inhibition of hiv-1 replication. additionally, hiv-1-infected patients often suffer from myelin degeneration in the central nervous system. these patients have elevated levels of sulfatide in the cerebrospinal fluid (csf) and anti-sulfatide antibodies in the serum. elevated levels of anti-sulfatide antibodies can cause demyelination. this is caused by the binding of the anti-sulfatide antibodies to the surface of the myelin sheath and/or the surface of schwann cells, which then activates a complete cascade of demyelination. also, advanced stage aids patients can develop guillain–barré syndrome (gbs). guillain–barré syndrome is classified as an acute autoimmune polyneuropathy, which specifically affects the peripheral nervous system of the infected patient. experimentation has shown that anti-sulfatide autoimmune antibodies may contribute to the development of guillain–barré syndrome in aids patients as well as the development of peripheral nervous system injury in hiv-1 infected patients. hepatitis c several patients with hepatitis c virus (hcv) associated with mixed cryoglobulinemia (mc) have elevated levels of anti-sulfatide antibodies in their blood plasma. mixed cryoglobulinemia (mc) is an immune disease, which typically presents with immune complex mediated vasculitis of the small vessels. it is believed there is a relationship between hcv and mc; however, the exact role of hcv in relation to the cause of mc has not yet been fully understood or discovered. nevertheless, sphingolipid synthesis in the host, has been demonstrated to be necessary for hcv replication, which indicates that sulfatide may be involved in the replication of hcv. influenza a influenza a virus (iav) binds strongly to sulfatide. however, sulfatide receptors have no sialic acid, which has been shown to play a necessary role as a virus receptor that facilitates the binding of the influenza a virus. sulfatide has also been shown to inhibit influenza a virus sialidase activity. however, this is only under acidic conditions not neutral conditions. to fully understand the role of sulfatide in the cycle of iav infection, research have expressed sulfatide in madin-darby canine kidney cells, which can express sulfatide and support iav replication and in cos-7 cells, which do not have the ability to express sulfatide and do not support iav replication sufficiently. consequently, the cos-7 cells were transfected with galactosyltransferase and cerebroside sulfotransferase genes from the madin-darby canine kidney cells and used to make two cell clones with the ability to express sulfatide . these cells were then infected with the iav virus, and research has shown that the sulfatide enhanced cells infected with iav show increased iav replication in the progeny virus, 500–3,000 times the parent virus. however, the sulfatide enriched cells also have a small reduction in initial infection compared to the parent cells. the opposite is shown in sulfatide knockdown madin-darby canine kidney cells, exhibiting a reduction in progeny virus concentration vs. parent virus concentration and an increase in initial infection. overall, such experiments demonstrate that sulfide rich cells enhance iav replication and that sulfatide on the cell's surface may play a role in the replication of iav. further experimentation has demonstrated that sulfatide enriched cells, in which sulfatide binds to hemagglutinin, enhances iav replication by increasing