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Glycosylated nanoparticles (NPs) have drawn a lot of attention in the biomedical field over the past few decades, particularly in applications like targeted drug delivery. Mannosylated NPs and mannan-binding lectins/proteins (MBL/MBP) are emerging as promising tools for delivery of drugs, medicines, and enzymes to targeted tissues and cells as nanocarriers, enhancing their therapeutic benefits while avoiding the adverse effects of the drug. The occurrence of plenty of lectin receptors and their mannan ligands on cell surfaces makes them multifaceted carriers appropriate for specific delivery of bioactive drug materials to their targeted sites. Thus, the present review describes the tethering of mannose (Man) to several nanostructures, like micelles, liposomes, and other NPs, applicable for drug delivery systems. Bioadhesion through MBL-like receptors on cells has involvements applicable to additional arenas of science, for example gene delivery, tissue engineering, biomaterials, and nanotechnology. This review also focuses on the role of various aspects of drug/antigen delivery using (i) mannosylated NPs, (ii) mannosylated lectins, (iii) amphiphilic glycopolymer NPs, and (iv) natural mannan-containing polysaccharides, with most significant applications of MBL-based NPs as multivalent scaffolds, using different strategies.Mannosylated NPs and/or MBL/MBP are coming up as viable and versatile tools as nanocarriers to deliver drugs and enzymes precisely to their target tissues or cells. The presence of abundant number of lectin receptors and their mannan ligands on cell surfaces makes them versatile carriers suitable for the targeted delivery of bioactive drugs.

Lactate dehydrogenase (LDH) is a terminating enzyme in the metabolic pathway of anaerobic glycolysis with end product of lactate from glucose. The lactate formation is crucial in the metabolism of glucose when oxygen is in inadequate supply. Lactate can also be formed and utilised by different cell types under fully aerobic conditions. Blood LDH is the marker enzyme, which predicts mortality in many conditions such as ARDS, serious COVID-19 and cancer patients. Lactate plays a critical role in normal physiology of humans including an energy source, a signaling molecule and a pH regulator. Depending on the pH, lactate exists as the protonated acidic form (lactic acid) at low pH or as sodium salt (sodium lactate) at basic pH. Lactate can affect the immune system and act as a signaling molecule, which can provide a "danger" signal for life. Several reports provide evidence that the serum lactate represents a chemical marker of severity of disease similar to LDH under inflammatory conditions. Since the mortality rate is much higher among COVID-19 patients, associated with high serum LDH, this article is aimed to review the LDH as a therapeutic target and lactate as potential marker for monitoring treatment response of inflammatory diseases. Finally, the review summarises various LDH inhibitors, which offer potential applications as therapeutic agents for inflammatory diseases, associated with high blood LDH. Both blood LDH and blood lactate are suggested as risk factors for the mortality of patients in serious inflammatory diseases.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a virus called "Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)." In the majority of patients, infection with COVID-19 may be asymptomatic or may cause only mild symptoms. However, in some patients, there can also be immunological problems, such as macrophage activation syndrome (CSS) that results in cytokine storm syndrome (CSS) and acute respiratory distress syndrome (ARDS). Comprehension of host-microbe communications is the critical aspect in the advancement of new therapeutics against infectious illnesses. Endogenous animal lectins, a class of proteins, may perceive non-self glycans found on microorganisms. Serum mannose-binding lectin (sMBL), as a part of the innate immune framework, recognizes a wide range of microbial microorganisms and activates complement cascade via an antibody-independent pathway. Although the molecular basis for the intensity of SARS-CoV-2 infection is not generally understood, scientific literature indicates that COVID-19 is correlated with unregulated activation of the complement in terms of disease severity. Disseminated intravascular coagulation (DIC), inflammation, and immune paralysis contribute to unregulated complement activation. Pre-existing genetic defects in MBL and their association with complement play a major role in immune response dysregulation caused by SARS-CoV-2. In order to generate anti-complement-based therapies in Covid-19, an understanding of sMBL in immune response to SARS-CoV-2 and complement is therefore essential. This review highlights the role of endogenous sMBL and complement activation during SARS-CoV-2 infection and their therapeutic management by various agents, mainly plant lectins, since antiviral mannose-binding plant lectins (pMBLs) offer potential applications in the prevention and control of viral infections.

Dug wells water is frequently used for irrigation of crops in India. The huge quantity of various toxic pollutants enters to ground water through anthropogenic and geogenic sources, which make the ground water, unfit for irrigation. Such water if used for irrigation may pose a serious risk to quality and quantity of crops and other things. The present study highlights the water quality monitoring of selected dug wells of Central India (Rajaula ward of Chitrakoot town). Different water quality parameters such as pH, electrical conductivity, Ca ++ , Mg ++ , Na + , K + , HCO 3 − , CO 3 − - chloride, sulfate, sodium percentage (Na %), magnesium hazards, sodium absorption ratio (SAR), residual sodium carbonate (RSC), potential soil salinity and permeability index were investigated for monitoring of t0 assess its suitability for irrigation. Some models, i.e. Wilcox Diagram, U.S. Salinity diagrams, Doneen criterion, etc. were also used for conformation of dug well water quality for irrigation purpose. Results of the study indicated that all selected wells have mostly medium and high salinity, under limit of SAR, medium Na%, medium Mg hazards, under limit of RSC and low Cl − quantity.

The lactate dehydrogenase (LDH) has been studied widely because it exists in various isozymic forms. The association of A and B subunits of LDH can generate five tetrameric isozymes, but the finding of the sixth isozyme in mature human testis and sperm indicated the presence of an additional subunit of LDH, designated as LDH-X (also termed LDH-C4 due to tetrameric nature of C-subunit). LDH-C4 isozyme is an iso-, allo-, and auto-antigen present in mammalian sperm cells. The synthesis of LDH-C4 in the testis takes place during sexual maturation, and it is the predominant fraction in mature spermatozoa. Though, originally considered to be testis specific, LDH-C or Ldh3 in mice was later detected in the murine oocyte and early embryo. Ldh3 in mouse supports its role in energy production in spermatids that favor lactate as substrate and in spermatozoa with a characteristic aerobic glycolytic path to yield ATP. During last two decades, cancer/testis-associated genes (CTAs) which are expressed only in the germinal epithelium of the testis are also expressed in some cancer cells, but not in non-cancerous somatic tissues. The CTAs are considered promising candidates for diagnosis and immunotherapy of cancer. The sperm-specific Ldh-c gene has been shown to express in a broad spectrum of human tumors, with high frequency in lung cancer, melanoma, and breast cancer; the protein being expressed virtually in all tumor types tested. Accordingly, LDH-C4 is the unique target for contraception in both males and females and offers potential future for immunotherapy of different types of cancers. As LDH-C has a preference for lactate as a substrate, LDH-C activation in cancer may depend on lactate for ATP production. The major aim of this article is to review the salient features of LDH-C subunit and the immune responses of LDH-C4 in homologous and heterologous species in relation to its role in acceptance or rejection of the allograft and its application in contraception and immunotherapy of cancer, directly or indirectly through the regulation of its substrate, the lactate.

Zusammenfassung Immunchemische Untersuchungen der sauren Phosphatase im menschlichen Seminalplasma Die saure Phosphatase des menschlichen Seminalplasmas wird in Gegenwart von normalem Kaninchenserum durch nicht-kompetetive Mechanismen gehemmt, wohingegen sich in Gegenwart von Kaninchenantiserum diese Verhaltnisse normalisierten und die Aktivitat stabilisiert wurde. Kinetische Untersuchungen uber die Stabilisierung der sauren Phosphatase durch Antiserum wurden mit L-Tartrat als spezifischem Hemmstoff der sauren Prostataphosphatase kombiniert. L-Tartrat hemmte das Enzym sowohl in Gegenwart als auch in Abwesenheit von normalem und Antiserum kompetetiv; der Prozentsatz der Hemmung bewegte sich in der gleichen Grosenordnung, was anzeigt, das das katalytische Zentrum des Enzyms die Bindung mit den Antikorpern gegen saure Phosphatase nicht in Mitleidenschaft zieht. Die Kinetik der Hitzedenaturierung der sauren Phosphatase last darauf schliesen, das die saure Phosphatase des Samens in Gegenwart und Abwesenheit von Normalserum hitzelabiler ist als in Gegenwart von Antiserum. Die Denaturierungstemperatur bei halber Anfangsaktivitat (T 1/2) in Gegenwart von Normal- und Antisera war 34° respektive 66° C. Die nicht-lineare Verteilung nach Arrhenius der Denaturierungsraten des Enzyms last auf verschiedene Konformationszustande wahrend der Denaturierung schliesen, wobei die Werte fur die Aktivierungsenergie Ea zwischen 20.08 und 5.03 Kcal bei 25° bis 65° C lagen.

Economic fluctuations refer to ups and downs in the levels and/or rates of changes in the economic goal variables like real national income (GOP), inflation rate, and the rate of unemployment. Stabilization policies are the tools in the hands of the policy-makers to counter economic fluctuations and these include fiscal policy, monetary policy, and foreign exchange rate policy. This paper analyses the extent and depth of all major fluctuations (business cycles) across the G-7 countries, India, China, Malaysia, and the world as a whole during the Great Oepression and the last 40 years, identifies the major cause behind each significant departure from the trend, and examines the theoretical limitations as well as the actual application of the various policies to tame those business cycles. This paper finds that: Business cycles are universal. Each of the countries under analysis here has experienced an overall positive growth rate but also a negative growth rate, generally in more than one year, during the period of this study. Further, the standard deviation of the growth rate as a percentage of the growth rate (called the coefficient of variation) is sizeable in all countries as it varies between a low of 41 per cent in Malaysia and a high of 96 per cent in the UK. Business cycles are not always synchronized across countries. During the Great Depression and stagflation periods, most countries suffered from similar maladies but such a synchronization was rarely found in other times. For example, Japan performed relatively better during the 1950s and 1960s, and China and the South-East Asian economies enjoyed that position during the 1980s and 1990s. Further, while every country has experienced a negative growth rate, there is no year in the last 50 years in which the growth rate was negative in all countries. The world as a whole, of course, has always enjoyed a positive growth rate. Business cycles have become milder over time. During the Great Depression, output fell by over two digit rates in many countries japan experienced a two-digit growth rate in most of the years during 1960s, 1980s, and 1990s, but lately, the growth rate in most countries is hovering around 2 to 5 per cent. Business cycles are caused by varying events. While the adverse demand shock caused the Great Depression, the adverse supply shock triggered the stagflation and economic reforms have been responsible for hyperinflation, financial crises, and prosperity. always been applied in the right perspective. During the Great Depression, the nominal money supply should have increased but it fell and the government expenditure rose but only marginally. The simple correlation and multiple regression analysis' results for the three select countries suggest that while the monetary policy was conducted as an anti-cyclical tool in lndia, it was pro-cyclical in the US and China, and quite the opposite was the case with regard to the conduct of fiscal policy. The cycles are bad and it is unfortunate that the stabilization policies do not offer panacea to tame them fully. However, it is heartening to find that economic fluctuations have become milder over time and the credit for this goes to the innovative developments in the macroeconomic theory and to the improvements in the practice of stabilization policies. Though cycles are unlikely to be eradicated, there is now only little fear of severe crises in future like the Great Depression or stagflation.

Steganography is the art and science of communicating in a way which hides the existence of the secret message in communication. Steganography is being used for hiding information in the text or images. This paper describes the use of this technique in the area of Group 3 fax communication. We have developed a software tool named as “Fax Image Analysis Tool (FIAT)” based on Pure Steganography Model to conceal a text or fax message in some other dummy fax document. A steganographic method suitable for Fax data, based on the principles of Substitution Steganographic Techniques, has been developed and implemented. Features to open a Fax file, analyse it and display the fax image along with corresponding bit stream of fax image have also been provided. These features can be used for steganalysis purposes.

Radiation inactivation of sperm specific lactate dehydrogenase-C4 (LDH-C4) has been studied and compared with the somatic LDH in aqueous solution. D37 of C isozyme was 470 Gy and that of B isozyme was 520 Gy. Semi-log plots of log N/No versus dose suggested that the inactivation of two LDH isozymes in presence of normal saline follows a single hit kinetics. Target molecular weight calculated by radiation analysis was found as 1.52 × 105 gm/mole for LDH-C4 and 1.38 × 105 gm/mole for LDH-B4. SDS-PAGE of irradiated enzymes showed a band of 35 kDa but did not indicate the presence of any other extra band, when compared with sham-irradiated enzymes. Chemical kinetics of residual activity following irradiation at D37 showed decrease in Vmax with coenzymes and primary substrates. However, decrease in Km was seen with pyruvate as increasing substrate. Nevertheless, Km did not change when NAD+ was the leading substrate for LDH-B4 or LDH-C4. A hyperchromicity in intrinsic fluorescence and a blue shift in λmax over sham-irradiated LDH-C4 revealed the exposure of buried tryptophan residues to the surface after radiation inactivation. Results suggest that inspite of presence of variant amino acids, the conformations of two isozymes are stabilized by similar forces which behave in a similar way for radiation inactivation in aqueous phase.

Toxicity of lead acetate after administration through the oral route at 0-50 mg/kg body weight of animal has been assessed in the liver of pregnant mice and compared with the effect in the liver of nonpregnant dams. Analysis showed that the basal level of hepatic lead is considerably reduced during pregnancy as compared to that in nonpregnant state. After administration of Pb-acetate, deposited lead in liver of nonpregnant mice was 3- to 4-fold while in pregnant mice was, it was 1.8- to 3.0-fold over their respective control values. Although hepatic Fe, Cu, and Zn levels had a tendency to be lowered during pregnancy, it appeared that the added trace quantity of lead prior to and during pregnancy helped in the retention of these metals, which either remained unaffected (as Fe) or declined (Cu and Zn) after lead administration during the nonpregnant state. The effect of lead on Mn diminution, however, was visible at the dose of 50 mg/kg body wt of lead-acetate. Alkaline phosphatase, which increased during pregnancy along with Mn, was reversed between the pregnant and nonpregnant states after oral administration of lead. On the other hand, the level of delta-aminolevolunic acid dehydratase, which declined during normal pregnancy, continued to fall further after lead exposure. It is concluded that the distribution of basal or administered lead and its effect on enzyme activities and trace metal composition in liver depends on the pregnant and nonpregnant states of female hosts.

Department of Chemistry, V. K. S. University, Ara-802 301, Bihar, India E-mail : hshe2503@rediffmal.com Department of Chemistry, Mahatma Gandhi Chitrakut Gramodaya Vishwavidyalya, Chitrakoot-485 331, Madhya Pradesh, India Manuscript received online 28 July 2012, revised 11 October, accepted 11 October 2013 Extensive studies on the electrical transport properties and its related phenomena due to the transfer of lithium ion in poly vinyl alcohol (PV A) complex have been reported. The complexed PV A has gained greater attention due to considerable change in the conducting behavior of the material. In order to bring an improvement in electrical and dielectrical properties of PV A a suitable dopant; hexahydrated lithium hydroxide is added and the complex of PV A in film form has been undertaken for its dielectric investigations. In the present article study of dielectric constant, dielectric loss and loss tangent of pure PV A and lithium hydroxide doped PV A was highlighted. The dielectric behavior of the complexes at different dopant concentrations (0, 5, 10 and 30%) has been observed by measuring capacitance and dielectric loss tangent of complexed PV A films at different frequencies and temperatures. &nbsp

The present study was undertaken to compare the effects of 10–50 mg/kg b.wt. of Pb acetate after chronic treatment through oral gavage on: (a) the distribution of trace elements such as Fe, Cu, Zn, and Mn, (b) enzyme activity of δ-amino levulinic acid dehydratase (δ-ALAD) and alkaline phosphatase, and (c) glutathione (GSH) in kidney and (d) δ-ALAD in blood of pregnant and non-pregnant mice. Treatment with Pb acetate was given on every alternate day for 4 weeks prior to mating and for 3–4 weeks until pregnancy became apparent and confirmed by laporatomy. Lead administration reduced the rate of reproduction as assessed by number of living viable embryos. During normal pregnancy renal Cu, Fe and GSH tended to decline although non-significantly and continued to do so after lead administration. Mn was considerably and significantly elevated, whereas activity of δ–ALAD (non-activated) was quite low in pregnant mice. Following administration of Pb acetate, kidneys of pregnant and non-pregnant dams accumulated Pb in a dose-dependent manner, but as compared to non-pregnant mice, Pb increase in pregnant dams was significantly lower. Pb toxicity was associated with the loss of δ-ALAD in blood and kidney, but unlike the non-activated form of δ-ALAD, the dithiothreitol-activated form of δ-ALAD declined in a significant amount. The residual activity showed a high degree of negative correlation with endogenous Pb as well as with Zn/Pb ratio. Pb toxicity did not modify renal Fe, Cu and Zn in the nonpregnant state, but reduced renal Fe during pregnancy. On the other hand, Mn decline is a sensitive indicator of Pb toxicity and correlated with the Pb content during pregnancy. While the increase in renal alkaline phosphatase activity in pregnancy persisted even after Pb administration up to 25 mg/kg b.wt. Pb acetate, the activity of alkaline phosphatase in non-pregnant mice did not change after lead treatment. The level of alkaline phosphatase did not correlate with the Zn content but correlated with endogenous levels of Pb, Mn or Zn/Mn ratio. Increase in GSH during the pregnant and nonpregnant state after Pb exposure was apparent. It appears that the body attempts to regulate the Pb toxicity by promoting self-defence by enhanced production of thiol compounds such as glutathione. It is concluded that pregnancy modifies renal lead retention and lead toxicity in terms of trace metal composition and some metalloenzymes.

Layilin, a ~55-kDa lectin, is a widely expressed integral membrane hyaluronan receptor, originally identified as a binding partner of talin located in membrane ruffles. It is recruited to membrane ruffles in cells induced to migrate in in vitro wounding experiments and in peripheral ruffles in spreading cells. Layilin is a transmembrane C-type lectin (Fig. 40.1) and binds specifically to hyaluronan (HA) but not to other tested glycosaminoglycans and belongs to group VIII of CTLDs. The other member of this group is chondrolectin. Layilin’s ability to bind hyaluronan reveals an interesting parallel between layilin and CD44, because both can bind to cytoskeleton-membrane linker proteins through their cytoplasmic domains and to hyaluronan through their extracellular domains. This parallelism suggests a role for layilin in cell adhesion and motility (Banerji et al. 1999; Bono et al. 2001). There is no sequence homology with known hyaluronan receptors, including CD44, RHAMM (receptor for HA-mediated motility), or LYVE-1 (lymphatic vessel endothelial HA receptor-1). Thus, by binding to HA, layilin may facilitate cell migration by mediating early interactions between spreading cells and the extracellular matrix (ECM). Since, hyaluronan is involved in invasion of a variety of tumor cells and layilin was detected in the human lung cell line A549, layilin might play crucial roles in lymphatic metastasis of lung carcinoma. Suppression of layilin expression by iRNA significantly increased survival of tumor-bearing mice. The suppression of layilin expression might be a promising strategy for treatment of human lung carcinoma (Chen et al. 2008).

In the immune system, C-type lectins and CTLDs have been shown to act both as adhesion and as pathogen recognition receptors. The Dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN) and its homologs in human and mouse represent an important C-type lectin family. DC-SIGN contains a lectin domain that recognizes in a Ca2+-dependent manner carbohydrates such as mannose-containing structures present on glycoproteins such as ICAM-2 and ICAM-3. DC-SIGN is a prototype C-type lectin organized in microdomains, which have their role as pathogen recognition receptors in sensing microbes. Although the integrin LFA-1 is a counter-receptor for both ICAM-2 and ICAM-3 on DC, DC-SIGN is the high affinity adhesion receptor for ICAM-2/-3. While cell–cell contact is a primary function of selectins, collectins are specialized in recognition of pathogens. Interestingly, DC-SIGN is a cell adhesion receptor as well as a pathogen recognition receptor. As adhesion receptor, DC-SIGN mediates the contact between dendritic cells (DCs) and T lymphocytes, by binding to ICAM-3, and mediates rolling of DCs on endothelium, by interacting with ICAM-2. As pathogen receptor, DC-SIGN recognizes a variety of microorganisms, including viruses, bacteria, fungi and several parasites (Cambi et al. 2005). The natural ligands of DC-SIGN consist of mannose oligosaccharides or fucose-containing Lewis-type determinants. In this chapter, we shall focus on the structure and functions of DC-SIGN and related CTLDs in the recognition of pathogens, the molecular and structural determinants that regulate the interaction with pathogen-associated molecular patterns. The heterogeneity of carbohydrate residues exposed on cellular proteins and pathogens regulates specific binding of DC-expressed C-type lectins that contribute to the diversity of immune responses created by DCs (van Kooyk et al. 2003a; Cambi et al. 2005).

Proteoglycans (PGs) are a diverse group of glycoproteins, which are formed through covalent and noncovalent aggregation of proteins and glycosaminoglycans (GAGs) in the extracellular matrix. GAGs are linear polysaccharides, whose building blocks (disaccharides) consist of an amino sugar (either GlcNAc or GalNAc) and an uronic acid (GlcA and IdoA). Virtually all mammalian cells produce proteoglycans and either secrete them into the ECM, insert them into the plasma membrane, or store them in secretory granules. The matrix proteoglycans include small interstitial proteoglycans (decorin, biglycan, fibromodulin), a proteoglycan form of type IX collagen, and one or more members of the aggrecan family of proteoglycans (aggrecan, brevican, neurocan, or versican). Some of these proteoglycans contain only one GAG chain (e.g., decorin), whereas others have more than 100 chains (e.g., aggrecan). The matrix proteoglycans typically contain the GAGs known as CS or DS. Exceptions to this generalization exist, since the HS proteoglycans perlecan and agrin are major species found in basement membranes. The size and shape of PGs vary widely that suggests numerous functions for them. The protein components of PGs are synthesized by ribosomes and translocated into the lumen of the rough endoplasmic reticulum. Glycosylation of the proteoglycan occurs in the Golgi apparatus in multiple enzymatic steps. The point of attachment is a Ser residue to which the glycosaminoglycan is joined through a tetrasaccharide bridge (For example: chondroitin sulfate-GlcA-Gal-Gal-Xyl-PROTEIN). The Ser residue is generally in the sequence -Ser-Gly-X-Gly- (where X can be any amino acid residue), although not every protein with this sequence has an attached glycosaminoglycan. Thus, a PG contains a core protein and one to many glycosaminoglycans or carbohydrate chains. Along with glycoproteins and glycolipids proteoglycans on the noncytosolic side of the cell membrane form the carbohydrate layer. This layer on top of the bilipid layer serves to protect the cell from both chemical and mechanical damage. The components absorb water, giving the cell a slimy surface. Another main function of PGs is to regulate the movement of molecules through the matrix. Proteoglycans also contribute to the activity and stability of proteins within the matrix.

Natural killer (NK) cell receptors belong to two unrelated, but functionally analogous gene families: the immunoglobulin superfamily, situated in the leukocyte receptor complex (LRC) and the C-type lectin receptors (CLRs) superfamily, located in the natural killer gene complex (NKC). Wong et al. (2009) described the largest NK receptor gene expansion seen to date and identified 213 putative C-type lectin NK receptor homologs in the genome of the platypus. Many have arisen as the result of a lineage-specific expansion. Orthologs of OLR1, CD69, KLRE, CLEC12B, and CLEC16p genes were also identified. The NKC is split into at least two regions of the genome: 34 genes map to chromosome 7, two map to a small autosome, and the remainder are unanchored in the current genome assembly. No NK receptor genes from the LRC were identified. The massive C-type lectin expansion and lack of Ig-domain-containing NK receptors represents the most extreme polarization of NK receptors found to date. This new data from platypus was utilized to trace the possible evolutionary history of the NK receptor clusters.

Chitinases (EC.3.2.1.14) hydrolyze the β-1,4-linkages in chitin, an abundant N-acetylglucosamine (GlcNAc) polysaccharide that is a structural component of protective biological matrices of invertebrate such as insect exoskeletons and fungal cell walls. Chitinases cleave chitin and contain the conserved sequence motif DXXDXDXE, in which the glutamate is the catalytic residue. Chitinases are found in species including archaea, bacteria, fungi, plants, and animals. On the basis of sequence homologies, chitinases fall into two groups: families 18 and 19 of glycosyl hydrolases. Members of family 18 employ a substrate-assisted reaction mechanism (van Aalten et al. 2001), whereas those of family 19 adopt a fold-and-reaction mechanism similar to that of lysozyme (Monzingo et al. 1996), suggesting that these families evolved independently to deal with chitin. The glycoside hydrolase 18 (GH18) family of chitinases is an ancient gene family widely expressed in archea, prokaryotes and eukaryotes. Since chitin is an important structural component of pathogens like fungi as well as a constituent of the mammalian diet, a dual function for mammalian chitinases in innate immunity and food digestion has been envisioned (Suzuki et al. 2002; Boot et al. 2005a). Indeed, for human chitotriosidase, an enzyme predominantly expressed by phagocytes, a fungistatic effect has been demonstrated (van Eijk et al. 2005). Several studies have tried to link a common chitotriosidase deficiency to susceptibility for infection by chitin-containing parasites (Bussink et al. 2006). The physiological function of the second mammalian chitinase, acidic mammalian chitinase (AMCase), has attracted considerable attention due to a report linking the protein to the pathophysiology of asthma (Zhu et al. 2004).

Natural killer cells are important component of the innate immune system, providing protection against intracellular infection particularly viruses and also neoplasia through direct cytotoxic mechanisms and the secretion of cytokines. They mediate their effects through direct cytolysis, release of cytokines and regulation of subsequent adaptive immune responses. They are called ‘natural’ killers because, unlike cytotoxic T cells, they do not require a previous challenge and preactivation to become active. NK cells can be activated by a range of soluble factors, including type I interferons, IL-2, IL-12, IL-15 and IL-18, but also by direct cell to cell contact between NK cell receptors and target cell ligands. NK cells possess an elaborate array of receptors, which regulate NK cytotoxic and secretory functions upon interaction with target cell MHC class I proteins. Determination of structures of NK cell receptors and their ligand complexes has led to a fast growth in our understanding of the activation and ligand recognition by these receptors as well as their function in innate immunity. B and T cells significantly and differentially influence the homeostasis and the phenotype of NK cells. The function of NK cell is tightly regulated by a fine balance of inhibitory and activating signals that are delivered by a diverse array of cell surface receptors. A prerequisite for a NK cell attack is the presence on target cells of ligands for activating receptors and low level or absence of ligands for inhibitory receptors. It was believed that NK self-tolerance was achieved by expression on each NK cell of at least one self-MHC specific inhibitory receptor. However, this dogma has been challenged after identification of a NK cell population in normal mice that lack inhibitory receptors specific for self-MHC class I molecules (Kumar and McNerney 2005; Fernandez et al. 2005). Therefore, it was made clear that some additional surface receptors contribute to NK self-tolerance and to the modulation of NK cell responses. The characterization and the identification of their physiological ligands allow us a comprehensive understanding of NK cell function.

Insulin and the insulin-like growth factors, IGF-I (IGF1) and –II (IGF2) are structurally related peptides that elicit a large number of similar biological effects in target cells. Three well-characterized receptor complexes bind one or more of these peptides with high affinity. Two of these receptors, denoted as type 1, are ligand-activated tyrosine kinases with similar heterotetrameric α2β2 subunit structures which bind insulin or IGF-1, respectively, with highest affinity. Ligand-stimulated tyrosine autophosphorylation of these receptors further activates their intrinsic tyrosine kinase activities both in vitro and in intact cells. Rapid signal transduction follows such receptor autophosphorylation and tyrosine kinase activation, leading to increased serine phosphorylation of many cell proteins and decreased serine phosphorylation of several others. A third receptor in this group binds IGF-1 and -2, lacks kinase activity and is denoted as type II IGF receptor (IGF2R). The cell surface receptor for IGF2 also functions as a cation-independent M6PR. Therefore, cation-independent mannose 6-phosphate receptor (CI-MPR) is also referred as insulin-like growth factor 2 receptor (IGF2R) or IGF2/MPR. The CI-MPR/IGF2R is a single transmembrane domain glycoprotein that plays a major role in the trafficking of lysosomal enzymes from the trans-Golgi network (TGN) to the endosomal-lysosomal (EL) system. This CI-MPR/IGF2R has also a potential role in growth factor maturation and clearance, and mediates IGF2-activated signal transduction through a G-protein-coupled mechanism. The IGF2R/CI-MPR rapidly recycles between the cell surface membrane and intracellular membrane compartments, providing for the rapid uptake of both IGF2 and M6P-linked lysosomal enzymes. Insulin action markedly increases the proportion of receptors in the plasma membrane and the uptake of bound ligands. Embryonic development and normal growth require exquisite control of IGFs (Dahms et al. 2008; Gary-Bobo et al. 2007).

L-type lectins possess a luminal carbohydrate recognition domain (CRD) that binds to high-mannose-type oligosaccharides in aCa2+-dependent manner. The L-type CRD is named after the lectins found in abundance in the seeds of leguminous plants, such as concanavalin A from jack beans. The history of L-type lectins is as old as discovery of plant lectins from seeds of leguminous plants in nineteenth century. The structural motifs of L-type lectins are now known to be present in a variety of glycan-binding proteins from other eukaryotic organisms. The domain is present in plant, fungal, and animal proteins, but plant and animal L-type lectins have divergent sequences and different molecular properties. While plant lectins are secreted-soluble proteins and found at high level in specialised tissues, animal L-type lectins are (often membrane-bound) luminal proteins that are found at low levels in many different cell types. This observation suggests that animal L-type lectins have different functions. The crystal structures of some of the legume seed lectins show structural similarities among these lectins and to some other lectins, including the galectins and a variety of other lectins. Therefore, the term “L-lectins” has been designated as a classification for all lectins with this legume seed lectin-like structure. The L-type lectin-like domain has an overall globular shape composed of a β-sandwich of two major twisted antiparallel β-sheets. The β-sandwich comprises a major concave β-sheet and a minor convex β-sheet, in a variation of the jelly roll fold (Velloso et al. 2002, 2003; Satoh et al. 2006, 2007).

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenic disorders, and globally is the third most common cause of end-stage kidney disease. Approximately 85% of ADPKD cases are attributable to mutations in polycystic kidney disease (PKD) gene 1 (PKD1) on chromosome 16, while mutations in PKD2 gene on chromosome 4 account for almost all of the remaining cases. These two diseases are phenotypically almost identical, differing only by the higher age of diagnosis with PKD2, and its slower progression to end-stage renal disease. The product of PKD1, polycystin-1 (PC-1), is a very large protein (4,303 amino acids), and is a membrane glycoprotein widely expressed in epithelial cells. It is also expressed in tight junctions, adherens junctions, desmosomes, apical junctions and primary cilia. Polycystin-2 (PC-2), the product of PKD2, is a smaller protein (968 amino acids) mainly present in the endoplasmic reticulum, but also in the cell plasma membrane. PC-1 and -2 are joined via a domain in the carboxy-tail of PC-1, and appear to act in concert (Ong and Harris 2005). PC-2 acts as a Ca2+ channel. It appears that PKD1 and PKD2 associate physically in vivo and may be partners of a common signaling cascade involved in tubular morphogenesis (Qian et al. 1997). Qian et al. (1997) defined naturally occurring pathogenic mutations of PKD1 and PKD2 that disrupt their associations. Portions of the cellular populations of PC-1 and PC-2 localize to the primary cilium. The ADPKD is the founding member of the “ciliopathies,” a recently defined class of genetic disorders that result from mutations in genes encoding cilia-associated proteins.

Glycan-recognizing proteins can be broadly classified into two groups: lectins (which typically contain an evolutionarily conserved carbohydrate-recognition domain (CRD) and sulfated glycosaminoglycan (SGAG)-binding proteins (which appear to have evolved by convergent evolution). The term “lectin” is derived from the Latin word legere, meaning, among other things, “to select”. Lectins are phylogenetically ancient and have specific recognition and binding functions for complex carbohydrates of glycoconjugates, i. e., glycoproteins, proteoglycans/glycosaminoglycans and glycolipids. Although lectins were first discovered more than 100 years ago in plants, they are now known to be present throughout nature and found in most of the organisms, ranging from viruses and bacteria to plants and animals. It is generally believed that the earliest description of a lectin was given by Peter Hermann Stillmark in his doctoral thesis in 1888 to the University of Dorpat. Stillmark isolated ricin, an extremely toxic hemagglutinin, from seeds of the castor plant (Ricinus communis) (Stillmark 1988). The animal hemagglutinins were noted quite early, almost in all invertebrates or lower vertebrates, but until the middle of the 1970s, only three of these (of eel, snail, and horseshoe crab) were isolated and characterized. The first of the animal lectins shown to be specific for a sugar (L-fucose) was from eel (Watkins and Morgan 1952). The isolation of the first mammalian lectin, the galactose-specific hepatic asialoglycoprotein receptor, was achieved by Gilbert Ashwell at the NIH and by Anatol G. Morell at the Albert Einstein Medical School (New York) in 1974 (Hudgin et al. 1974; Stockert et al. 1974). At the same time, Teichberg et al. 1975 isolated a β-galactose-specific lectin from electric eel that was designated galectins (Barondes et al. 1994), of which 15 members so far have been characterized. Since the beginning of 1980s, the number of purified animal lectins started to grow quickly, largely thanks to the advent of recombinant techniques.

Lectins recognize and bind carbohydrates covalently linked to proteins and lipids on the cell surface and within the extracellular matrix, and they mediate many cellular functions ranging from cell adhesion to pathogen recognition. Phylogenetically conserved family of Galectins was defined in 1994 as a shared consensus of amino-acid-sequences of about 130 amino acids and the CRD responsible for s-galactoside binding (Barondes et al. 1994). The galectin (Gal) CRDs bind small β-galactosides/poly-N-acetyllactosamine-enriched glycoconjugates. But the overall binding affinity for more complex glycoconjugates varies substantially. To date, 15 members of the mammalian galectin family have been identified. Some, such as galectin-1, are isolated as dimers and have a single CRD in each monomer, whereas others, such as galectin-4, are isolated as monomers and have two CRDs in a single polypeptide chain. While CRDs of all galectins share an affinity for minimum saccharide ligand N-acetyllactosamine—a common disaccharide found on many cellular glycoproteins—individual galectins can also recognize different modifications to this minimum saccharide ligand and so demonstrate the fine specificity of certain galectins for tissue- or developmentally-specific ligands (Ahmad et al. 2004a). Location studies of galectins have established that these proteins can segregate into multiple cell compartments in function of the status of the cells in question (Danguy et al. 2002; Liu and Rabinovich 2005). Although galectins as a whole do not have the signal sequence required for protein secretion through usual secretory pathway, some galectins are secreted and are found in the extracellular space. While the intracellular activity of galectin-1 is mainly independent on its lectin activity, its extracellular activity is mainly dependent on it. The functions and distribution of Gal-1 and Gal-3 are well characterized.

In eukaryotic cells, post-translational modification of secreted proteins and intracellular protein transport between organelles are ubiquitous features. One of the most studied systems is the N-linked glycosylation pathway in the synthesis of secreted glycoproteins (Schrag et al. 2003). The N-linked glycoproteins are subjected to diverse modifications and are transported through ER and Golgi apparatus to their final destinations in- and outside the cell. Incorporation of cargo glycoproteins into transport vesicles is mediated by transmembrane cargo receptors, which have been identified as intracellular lectins. For example, mannose 6-phosphate receptors (Ghosh et al. 2003) function as a cargo receptor for lysosomal proteins in the trans-Golgi network, whereas ERGIC-53 (Zhang et al. 2003) and its yeast orthologs Emp46/47p (Sato and Nakano 2002) are transport lectins for glycoproteins that are transported out of ER.

Sialic-acid-binding immunoglobulin-like lectins (Siglecs) bind sialic acids in different linkages in a wide variety of glycoconjugates. These membrane receptors are expressed in a highly specific manner, predominantly within haematopoietic system. Activating and inhibitory receptors act in concert to regulate cellular activation. Second sub-set of rapidly evolving siglecs is designated the CD33-related siglecs. In humans, these include CD33 and siglecs-5, -6, -7 (7/p75/AIRM1), -8, -9, 10, -11, -14 and -16, whereas, in mice, they comprise murine CD33 and siglec-E, -F, -G and -H. CD33 is a myeloid-specific inhibitory receptor, which along with CD33-related Siglecs represent a distinct subgroup that is undergoing rapid evolution. The structural features of CD33-related Siglecs and the frequent presence of conserved cytoplasmic signaling motifs point to their roles in regulating leukocyte functions that are important during inflammatory and immune responses. McMillan and Crocker (2008) reviewed ligand binding preferences and described the functional roles of CD33-related Siglecs in the immune system and the potential for targeting novel therapeutics against these surface receptors. Siglec-4 belonging to subset 1 of sialoadhesin family is discussed in Chap. 16.

CD93 is a ~120 kDa O-sialoglycoprotein that within the hematopoietic system is selectively expressed on cells of the myeloid lineage. CD93 in humans is encoded by the CD93 gene (Nepomuceno et al. 1997; Webster et al. 2000). CD93 is a C-type lectin transmembrane receptor which plays a role not only in cell–cell adhesion processes but also in host defence. CD93 belongs to the Group XIV C-Type lectin family, a group containing two other members, endosialin (CD248) and thrombomodulin (TM, CD141), a well characterized anticoagulant. All of them contain a C-type lectin domain, a series of epidermal growth factor like domains (EGF), a highly glycosylated mucin-like domain, a unique transmembrane domain and a short cytoplasmic tail. Due to their strong homology and their close proximity on chromosome 20, CD93 has been suggested to have arisen from thrombomodulin gene through a duplication event. Sequence analysis revealed that CD93 is identical to a protein on human phagocytes termed C1q receptor (C1qRp). The mouse homologue of human C1qRp is known as AA4. The AA4 and TM are derived from a common ancestor since both genes are co-localized to the same region of the chromosome 2 and also because they share similar domain composition and organization.

The extracellular matrix (ECM) is a complex molecular framework that provides physical support to cells and tissues, while also providing signals for cell growth, migration, differentiation and survival. Proteoglycans, as part of the extracellular or cell-surface milieu of most tissues and organ systems, play important roles in morphogenesis by modulating cell-matrix or cell-cell interactions, cell adhesiveness, or by binding and presenting growth and differentiation factors. The basic concept, that specialized extracellular matrices rich in hyaluronan, chondroitin sulfate proteoglycans (CS-PG: aggrecan, versican, neurocan, brevican, phosphacan), link proteins and tenascins (Tn-R, Tn-C) can regulate cellular migration and axonal growth and thus, actively participate in the development and maturation of nervous system, has gained rapidly expanding experimental support (Zimmermann and Dours-Zimmermann 2008). The distribution of ECM molecules displays area-specific differences along the dorso-ventral axis, delimiting functionally and developmentally distinct areas. In gray matter, laminae I and II lack PNNs of extracellular matrix and contain low levels of chondroitin sulfate glycosaminoglycans (CS-GAGs), brevican, and tenascin-R, possibly favoring the maintenance of local neuroplastic properties. Conversely, CS-GAGs, brevican, and phosphacan were abundant, with numerous thick PNNs, in laminae III-VIII and X. Motor neurons (lamina IX), surrounded by PNNs, containd various amounts of CS-GAGs (Vitellaro-Zuccarello et al. 2007).

A novel lectin family “F-type” constituted by a large number of proteins exhibit greater multiples of F-type motif, either tandemly arrayed or in mosaic combinations with other domains, including a putative transmembrane receptor that suggests an extensive functional diversification of this lectin family. F-type domains are found in proteins from a range of organisms from bacteria to vertebrates, but exhibit patchy distribution across different phylogenetic taxa suggesting that F-type lectin genes have been selectively lost even between closely related lineages, and making it difficult to trace the ancestry of the F-type domain. F-type lectins were first characterized in eels, which are teleost fish. Teleost fish species commonly have a number of F-type lectins (containing multiple tandem F-type domains) resulting from gene duplication events that have occurred independently in different teleost fish lineages. The F-type domain has clearly gained functional value in fish, whereas the fate of F-type domains in higher vertebrates is not clear, rather it has become defunct. While the functions of many F-type lectins have not yet been characterized, a pathogen-recognition role has been established for F-type lectin-like proteins in both invertebrates (e.g. the horseshoe crab Tachypleus tridentatus) and vertebrates (e.g. the Japanese eel Anguilla japonica). The F-type lectin fold from Anguilla anguilla agglutinin (AAA) (Bianchet et al. 2002) is widely distributed in proteins from horseshoe crabs to amphibians, with some representatives proposed to play a role in immunity (Honda et al. 2000; Saito et al. 1997). Although AAA and the rat MBL specifically recognize terminal L-fucose, they do so through differing binding interactions (Ng et al. 1996), which illustrate convergent functional properties among unrelated lectin families. Interestingly, the F-type fold is also shared with several proteins of distinct functional properties, including C-terminal domain of blood coagulation factors V and VIII, C-terminal domain of bacterial sialidases, N-terminal domain of fungal galactose oxidase, a human ubiquitin ligase subunit APC10/DOC1, a domain of single-strand DNA repair protein XRCC1, the b1 domain of neuropilin, and yeast allantoicase (Odom and Vasta 2006) pointing towards an ancient origin for F-type fold. The structural analogy of these seemingly unrelated proteins is indicative of the archaic origin of this lectin fold. Proteins from fish and amphibians with a range of domain organizations contain F-type domains, most of which are likely to bind fucose based on the conservation of key residues. The single-domain F-type lectins found in eels, which represent an early branch of teleost fish, are generally not found in modern teleosts, having been replaced by tandem two-domain proteins in species including striped bass (Morone saxatilis), zebrafish (Danio rerio), pufferfish (Tetraodon nigroviridans and Fugu rubripes) and stickleback (Gasterosteus aculeatus). In two-domain F-type lectins, both domains feature the fucose and Ca2+-binding residues, but the N-terminal domain lacks one inter-strand disulfide bond, and the C-terminal domain lacks the adjacent cysteines in loop 4, which may affect sugar binding. In four-domain tandem F-type lectins, which are exclusive to trout species (e.g. Oncorhynchus mykiss), the first and second domains lack the adjacent cysteines, and the second domain has strikingly lost all three residues from His/Arg/Arg triad, suggesting that fucose binding has been lost in this domain.

Historically the C-Type lectins (CLEC) or C-type lectin receptors (CLR) form a family of Ca2+ dependent carbohydrate binding proteins which have a common sequence motif of 115–130 amino acid residues, referred to as the carbohydrate recognition domain (CRD). The C-type designation is from their requirement for calcium for binding. The C-type lectin superfamily is a large group of proteins which is characterized as having at least one carbohydrate recognition domain (CRD), which has been found in more than 1,000 proteins, and it represents a ligand-binding motif that is not necessarily restricted to binding sugars (Drickamer 1999). Proteins that contain C-type lectin domains have a diverse range of functions including cell-cell adhesion, immune response to pathogens and apoptosis. However, many C-type lectins actually lack calcium- and carbohydrate-binding elements and thereby have been termed C-type lectin-like proteins. The CRD has four cysteines that are perfectly conserved and involved in two disulfide bonds. The CRD has been found in various kinds of proteins such as hepatic asialoglycoprotein receptor, lymphocyte IgE receptor, mannose binding protein, selectins (Drickamer 1999; Lasky et al. 1989) and proteoglycan core protein. Their functions include complement activation, endocytosis, cell recognition, defense mechanism, and morphogenesis (Drickamer 1999; Weis et al. 1998). Many evolutionarily related sequences belonging to the C-type lectins do not show overall sequence similarity. However, they have been classified on the basis of four cysteine residues, being involved in disulfide bridging, which are the trademark of this domain type. The framework surrounding this domain type can be very different from its C-terminal location in the collectins. The monomeric and membrane bound selectins have an N-terminal C-type lectin domain that mediates adhesion between certain cell types through carbohydrate binding. Other proteins, such as phospholipase A2 receptor and the macrophage mannose receptor, contain multiple copies of C-type lectin domains within a single polypeptide. Proteins possessing C-type lectin-like domain (CTLD) type are not necessarily lectins. Type II antifreeze protein present in some arctic fish and the mammalian pancreatic stone protein bind to and inhibit the growth of ice and calcium carbonate crystals, respectively (Hakansson and Reid 2000) and hence are not exactly CLEC but form a part of CTLD.

The pentraxins (PTX) are a superfamily of plasma proteins that are involved in innate immunity in invertebrates and vertebrates. They contain L-type lectin folds and require Ca2+ ions for ligand binding. Three of the principal members of the pentraxin family are serum proteins: namely, C-reactive protein (CRP), serum amyloid P component protein (SAP), and female protein (FP). PTX3 (or TSG-14) protein is a cytokine-induced protein that is homologous to CRPs and SAPs, but its function has not yet been determined. Beckmann et al. (1998) identified the superfamily of protein modules comprising the pentraxin families. Beckmann et al. (1998) predicted a jellyroll fold for all members of this superfamily. Pentraxins are made up of five noncovalently bound identical subunits that are arranged in a annular pentameric disc in shape. Proteins with this type of configuration are known as pentraxins. Based on the primary structure of the subunit, the pentraxins are divided into two groups: short pentraxins and long pentraxins. C-reactive protein (CRP), the first innate immunity receptor and serum amyloid P-component (SAP) are the two short pentraxins. Soluble pentraxins act as pattern recognition receptors with a dual role: protection against extracellular microbes and autoimmunity. The prototype protein of the long pentraxin group is pentraxin 3 (PTX3). The “long pentraxins” are an emerging family of genes that have conserved in their carboxy-terminal halves a pentraxin domain homologous to the prototypical acute phase protein pentraxins (CRP and SAP component) and acquired novel amino-terminal domains. Long pentraxins, including the prototype PTX3, are expressed in a variety of tissues and cells and in particular by innate immunity cells and most notably by dendritic cells and macrophages, in response to Toll-like receptor (TLR) engagement and in response to proinflammatory signals. PTX3 interacts with several ligands, including growth factors, extracellular matrix components and selected pathogens, playing a role in complement activation and facilitating pathogen recognition by phagocytes. Some long pentraxins are expressed in the brain and some are involved in neuronal plasticity and degeneration. PTX3 acts as a functional ancestor of antibodies, recognizing microbes, activating complement, and facilitating pathogen recognition by phagocytes, hence playing a non-redundant role in resistance against selected pathogens. In addition, PTX3 is essential in female fertility because it acts as a nodal point for the assembly of the cumulus oophorus hyaluronan-rich extracellular matrix. Thus, the prototypic long pentraxin PTX3 is a multifunctional soluble pattern recognition receptor at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility. Unlike the classical pentraxins, the PTX3 is expressed after exposure to the inflammatory cytokines to IL-1β and TNF-α, but not to IL-6, in various cell types. PTX3 has been shown to be produced in response to microbial infections, and highly elevated levels have been reported in patients with sepsis (al-Ramadi et al. 2004; Bottazzi et al. 2006; Garlanda et al. 2005; Mantovani et al. 2006).

Dendritic cells (DCs) are special subsets of antigen presenting cells characterized by their potent capacity to activate immunologically naive T cells to induce initial immune responses. DCs are far more potent than macrophages and B cells in their capacity to activate immunologically naive T cells. Infact, DCs are responsible for initiating T cell-mediated immune responses to a variety of antigens. Members of the DC family are distributed to virtually all the organs (except the brain), where they serve as tissue resident APCs, playing critical roles in presenting environmental, microbial, and tumor-associated antigens to the immune system. DCs operate at the interface of innate and acquired immunity by recognizing pathogens and presenting pathogen-derived peptides to T lymphocytes. As a component of the innate immune system, DCs organize and transfer information from the outside world to the cells of the adaptive immune system. DCs can induce such contrasting states as active immune responsiveness or immunological tolerance. Recent years have brought a wealth of information regarding DC biology and pathophysiology that shows the complexity of this cell system. Presentation of an antigen by immature (non-activated) DC leads to tolerance, whereas mature, antigen-loaded DCs are geared towards the launching of antigen-specific immunity.

Inflammation is defined as the normal response of living tissue to injury or infection. It is important to emphasize two components of this definition. First, that inflammation is a normal response and, as such, is expected to occur when tissue is damaged. Infact, if injured tissue does not exhibit signs of inflammation this would be considered abnormal and wounds and infections would never heal without inflammation. Secondly, inflammation occurs in living tissue, hence there is need for an adequate blood supply to the tissues in order to exhibit an inflammatory response. The inflammatory response may be triggered by mechanical injury, chemical toxins, and invasion by microorganisms, and hypersensitivity reactions. Three major events occur during the inflammatory response: the blood supply to the affected area is increased substantially, capillary permeability is increased, and leucocytes migrate from the capillary vessels into the surrounding interstitial spaces to the site of inflammation or injury. The inflammatory response represents a complex biological and biochemical process involving cells of the immune system and a plethora of biological mediators. Cell-to-cell communication molecules such as cytokines play an extremely important role in mediating the process of inflammation. Inflammation and platelet activation are critical phenomena in the setting of acute coronary syndromes. An extensive exposition of this complex phenomenon is beyond the scope of this article (Rankin 2004).

NKG2 receptors are type II C-type, lectin-like, integral membrane glycoproteins, which are expressed on the cell surface as heterodimers with CD94, which is an invariant type II C-type, lectin-like polypeptide. CD94 lacks a cytoplasmic tail and therefore, cannot transduce signals. It is however essential for the expression of NKG2 receptors. Four distinct genes, A/B, C, E/H, and F, encode the NKG2 receptors. Of these receptors, CD94/NKG2A is an inhibitory one, as it contains a long cytoplasmic tail with two ITIMs. Others have short cytoplasmic tails, and each associates noncovalently with a homodimer of DAP-12, as in the case of activating KIRs. The NKG2 family of genes (HGMW-approved symbol KLRC) contains at least six members (NKG2-A, -B, -C, -E, -F and -H) which are localized to human chromosome 12p12.3-p13.2, in the same region where CD69 genes have been mapped. In addition, the human CD94 and NKR-P1A genes map to the short arm of chromosome 12. The physical distance spanned by NK gene complex (NKC) in humans ranges between 0.7 and 2.4 megabases (Renedo et al. 1997). The NKG2 and CD94 genes are localized in a small region (< 350 kb) and mapped in the following order: (NKG2-C/NKG2-A)/NKG2-E/NKG2-F/NKG2-D/CD94. Sequence analysis of 62 kb spanning the NKG2-A, -E, -F, and -D loci allowed the identification of two LINE elements that could have been involved in the duplication of the NKG2 genes. Presence of one MIR and one L1ME2 element at homologous positions in the NKG2-A and NKG2-F genes is consistent with the existence of rodent NKG2 gene(s). The 5′-ends of the NKG2-A transcripts were mapped into two separate regions showing the existence of two separate transcriptional control regions upstream of the NKG2-A locus and defining putative promoter elements for these genes (Plougastel and Trowsdale 1998). Restriction mapping and sequencing revealed the NKG2-C, -D, -E, and -F genes to be closely linked to one another, and of the same transcriptional orientation. The NKG2-C, -E, and -F genes, despite being highly similar, are variable at their 3′ ends. It was found that NKG2-C consists of six exons, whereas NKG2-E has seven, and the splice acceptor site for the seventh exon occurs in an Alu repeat. NKG2-F consists of only four exons and part of exon IV is in some cases spliced to the 5′ end of the NKG2-D transcript. NKG2-D has only a low similarity to the other NKG2 genes Glienke et al. (1998). The murine NKG2-D-like sequence also maps to the murine NK complex near CD94 and Ly49 family members.

The R-type lectins are members of a superfamily of proteins, all of which contain a carbohydrate-recognition domain (CRD) that is structurally similar to the CRD in Ricin. The R-type domain is an ancient type of protein fold that is found in many glycosyltransferases as well as in bacterial and fungal hydrolases. Interestingly, the R-type CRD is the only one conserved between animal and bacterial lectins (Sharon and Lis 2004). Ricin was the first lectin discovered and it is the prototypical lectin in this category. Two different lectins have been purified from R. communis seeds, and in the original nomenclature they were termed RCA-I and RCA-II. RCA-I is an agglutinin but a very weak toxin. RCA-II is commonly called ricin, and it is both an agglutinin and a very potent toxin. The designation RCA-II has now been dropped, but the original name for the agglutinin RCA-I has been retained. The molecular mass of RCA-I is approximately 120 kDa and that of ricin is approximately 60-kDa. Ricin is a type II ribosome-inactivating protein (RIP-II). Although one might predict that RCA-I also would be highly toxic, it has weak activity compared to ricin because it lacks a separate A chain (Fig. 14.1).

When a blood vessel is injured, control of bleeding starts with the rapid adhesion of circulating platelets to the site of damage. Within seconds, the adhered platelets are activated, secrete the contents of storage organelles, spread out over the damaged area and recruit more platelets to the developing thrombus. However, if this process occurs in a diseased, sclerotic or occluded vessel, the resulting platelet thrombus may break away and block the coronary artery, causing a heart attack, or restrict blood supply to the brain, causing a stroke. The glycoprotein (GP) Ib-IX-V complex, a member of the leucine-rich protein family, is a constitutive platelet membrane receptor for von Willebrand Factor (vWF), a multimeric adhesive glycoprotein found in the matrix underlying the endothelial cell lining of the blood vessel wall and in the plasma. Binding of vWF to the Ib-IX-V complex regulates adhesion of platelets to the sub-endothelium at high shear flow, and initiates signal transduction leading to platelet activation. The GP Ib-IX-V complex also constitutes a binding site for α-thrombin, an interaction that facilitates thrombin-dependent platelet activation. Analysis of GP Ib-IX-V complex and vWF has identified discrete amino acid sequences that mediate their interaction. An anionic/sulfated tyrosine sequence of the GP Ib α-chain that is critical for binding of Ib-IX-V complex to both vWF and α-thrombin is analogous to sulfated anionic amino acid sequences mediating interactions of other adhesive proteins, including P-selectin binding to PSGL-1 and Factor VIII binding to vWF (Andrews et al. 1997).

Protein quality control in the endoplasmic reticulum (ER) is an elaborate process conserved from yeast to mammals, ensuring that only newly synthesized proteins with correct conformations in the ER are sorted further into the secretory pathway. The ER discriminates between native and nonnative protein conformations, selectively transporting properly folded proteins to their final destinations through the secretory pathway, or alternatively, retrotranslocating misfolded proteins to the cytosol to be degraded by proteasomes. In the quality control process, high-mannose type N-glycans play important roles in protein-folding events. Proteins that fail to achieve proper folding or proper assembly are degraded in a process known as ER-associated degradation (ERAD). The ERAD pathway comprises multiple steps including substrate recognition and targeting to the retro-translocation machinery, retrotranslocation from the ER into the cytosol, and proteasomal degradation through ubiquitination. The quality-control system also surveys the ER lumen for terminally misfolded proteins. Polypeptides singled out by this system are ultimately degraded by the cytosolic ubiquitin-proteasome pathway. Key components of both the ER quality-control system and the ERAD machinery have been identified, but a connection between the two systems has remained elusive (Yoshida and Tanaka 2010). Recent studies have documented the important roles of sugar-recognition (lectin-type) molecules for trimmed high-mannose type N-glycans and glycosidases in the ERAD pathways in both ER and cytosol. Since the ER is distributed throughout the cytosol, studies suggest that the cytosolic face of the ER membrane serves as a “platform” for degradation of misfolded cytosolic proteins (Metzger et al. 2008). The fundamental system that monitors glycoprotein folding in the ER and the unique roles of the sugar-recognizing ubiquitin ligase and peptide:N-glycanase (PNGase) in the cytosolic ERAD pathway has been reviewed (Yoshida and Tanaka 2010).

Glycoprotein folding and degradation in endoplasmic reticulum (ER) is mediated by ER quality control system. Quality control in ER ensures that only properly folded proteins are retained in the cell through mechanisms that recognize and discard misfolded or unassembled proteins in a process called endoplasmic reticulum-associated degradation (ERAD). The ERAD pathway comprises multiple steps including substrate recognition and targeting to the retro-translocation machinery, retrotranslocation from the ER into the cytosol, and proteasomal degradation through ubiquitination. Roles of lectin-type molecules for trimmed high-mannose type N-glycans and glycosidases in the ERAD pathways in both ER and cytosol has been documented in recent years. Yoshida et al. (2010) reviewed the fundamental system that monitors glycoprotein folding in the ER and the unique roles of sugar-recognizing ubiquitin ligase and peptide:N-glycanase (PNGase) in the cytosolic ERAD pathway. Mannose trimming plays an important role by forming specific N-glycans that permit the recognition and sorting of terminally misfolded conformers for ERAD. The EDEM (ER degradation enhancing α-mannosidase-like protein) subgroup of proteins belonging to Class I α1,2-mannosidase family (glycosylhydrolase family 47) has been shown to enhance ERAD. However, the mechanisms of substrate recognition and sorting to the ERAD pathway are poorly defined.

Regenerating (Reg) gene is a multigene super-family grouped into four subclasses, types I, II, III, and IV based on the primary structures of the encoded proteins and represents the products of small secretory proteins, which can function as acute phase reactants, lectins, antiapoptotic factors or growth factors for pancreatic β-cells, neural cells and epithelial cells in the digestive system. Among C-type lectin gene superfamily, the Reg-related genes are classified in group VII and encode small secreted proteins with a single carbohydrate recognition domain linked to a short N-terminal peptide (Drickamer 1999; Zhang et al. 2003a). The genes coding these proteins are tandemly clustered on chromosome 2p12 in humans and may have arisen from the same ancestral gene by gene duplication. The expression of this group of proteins is controlled by complex mechanisms, some members being constitutively expressed in certain tissues while, in others, they require activation by several factors. These members have several apparently unrelated biological effects, depending on the member studied and the target cell. insoluble fibrils at physiological pH (Iovanna and Dagorn 2005).

Information on receptor ligand systems used by NK cells to specifically detect transformed cells has been accumulating rapidly. Killer cell lectin-like receptor subfamily K, member 1, also known as KLRK1, is the product of human gene. The KLRK1 has been designated as CD314 and contains a C-type lectin-like domain (CTLD). KLRK1 is also known as: KLR; NKG2D; NKG2-D; FLJ17759; FLJ75772; D12S2489E. Human NKG2D was originally identified in 1991 as an orphan receptor on NK cells (Houchins et al. 1991). Although genetically mapping near the C-type lectin receptors CD94 and NKG2A-E, the NKG2D activating NK cell receptor has little sequence homology with these receptors and is expressed as a homodimer that signals through DAP10 rather than CD94 (Chap. 30). NKG2D binds to two distinct families of ligands, the MHC class I chain-related peptides (MICA and MICB) and the UL-16 binding proteins (ULBP). These ligands are upregulated in cells that have undergone neoplastic transformation, and NK cytotoxicity on tumor cells correlates with tumor expression of MICA and ULBP. The NKG2D differs from other members of the NKG2 family in significant ways. They do not form heterodimers with CD94 on the cell surface. Instead, they are expressed as homodimers, and each homodimer associates noncovalently with a homodimer of the adaptor protein DAP-10. The cytoplasmic tail of DAP-10 carries a YxxM motif, which can recruit the regulatory subunit p85 of phosphatidylinositol-3 kinase and Grb2 (see also Chap. 30).

In earlier Chapters we discussed mouse and human NK cell lectin receptors which can deliver inhibitory or activatory NK cell cytotoxicity in presence or absence of MHC-I molecules. Among non-lectin inhibitory receptors, killer immunoglobulin (Ig)-like receptors (KIRs) recognize different allelic groups of HLA-A, -B or -C molecules. ILT2 (or LIR-1) receptors are more ‘promiscuous’, as they recognize a large number of HLA class I alleles, while CRD containing CD94-NKG2A recognizes HLA-E, an HLA class I molecule with a limited polymorphism. It is well known that various HLA class I alleles provide signal sequence peptides that bind HLA-E and enable it to be expressed on the cell surface. Importantly, each type of KIR is expressed only by a subset of NK cells (Braud et al. 1998). A common characteristic of the various HLA class I-specific inhibitory receptors is the presence, in their cytoplasmic tail, of ITIM that enable them to recruit and activate SHP-1 and SHP-2 phosphatases (Moretta et al. 2001; Lanier 1998). In turn, these phosphatases switch off the activating signaling cascade initiated by the various activating receptors (Moretta and Moretta 2004). In this chapter we continue discussing cytotoxic receptors which do not depend on HLA antigens for their action and do not contain ITIM motif in their cytoplasmic tail as well as activating NK cell receptors which are of recent origin but do not contain lectin-like domain till date.

Cell adhesion molecules are glycoproteins expressed on the cell surface and play an important role in inflammatory as well as neoplastic diseases. There are four main groups: the integrin family, the immunoglobulin superfamily, selectins, and cadherins. The integrin family has eight subfamilies, designated as β1 through β8. The most widely studied subfamilies are β1 (CD29, very late activation [VLA] members), β2 (leukocyte integrins such as CD11a/CD18, CD11b/CD18, CD11c/CD18, and αd β2), β3 (CD61, cytoadhesions), and β7 (α4 β7 and αE β7). The immunoglobulin superfamily includes leukocyte function antigen-2 (LFA-2 or CD2), leukocyte function antigen-3 (LFA-3 or CD58), intercellular adhesion molecules (ICAMs), vascular adhesion molecule-1 (VCAM-1), platelet-endothelial cell adhesion molecule-1 (PE-CAM-1), and mucosal addressin cell adhesion molecule-1 (MAdCAM-1). The selectin family includes L-selectin (CD62L), P-selectin (CD62P), and E-selectin (CD62E). Cadherins are major cell-cell adhesion molecules and include epithelial (E), placental (P), and neural (N) subclasses. The binding sites (ligands/receptors) are different for each of these cell adhesion molecules (e.g., ICAM binds to CD11/CD18; VCAM-1 binds to VLA-4). The specific cell adhesion molecules and their ligands that may be involved in pathologic conditions and potential therapeutic strategies by modulating the expression of these molecules have been discussed (Elangbam et al. 1997). The main classes of adhesion molecule involved in lymphocyte interactions are the selectins, the integrins, members of the Ig superfamily, and some mucinlike molecules. Most adhesion molecules play fairly broad roles in the generation of immune responses. The three selectins act in concert with other cell adhesion molecules (e.g., intracellular adhesion molecule (ICAM-1), vascular cell adhesion molecule- 1 (VCAM-1), and leukocyte integrins (Springer 1990; Shimizu et al. 1992) to effect adhesive interactions of leukocytes, platelets, and endothelial cells. Hence selectins which belong to C-type lectins family are reviewed in Chaps. 21–23.

E-selectin, also known as CD62 antigen-like family member E (CD62E), endothelial-leukocyte adhesion molecule 1 (ELAM-1), or leukocyte-endothelial cell adhesion molecule 2 (LECAM2), is a cell adhesion receptor expressed on endothelial cells activated by cytokines. Like other selectins, it plays an important part in inflammation. In humans, E-selectin is encoded by the E-sel gene. E-selectin or ELAM-1is a member of the lectin/epidermal-growth-factor/complement-regulatory-protein-like cell-adhesion molecule family, which includes structurally related molecules referred to as selectins. Whereas P-selectin is stored in Weibel-Palade bodies, and it reaches the plasma membrane after exocytosis of these granules, E-selectin is not stored, and its synthesis is induced by cytokines. The fate of E-selectin has been studied after its surface expression following the intracellular routing of internalized antibodies to the selectin. After a brief surface exposure, internalized E-selectin is degraded in the lysosomes, whereas P-selectin returns to the storage granules from where it can be reused (Subramaniam et al. 1993). The presence of selectins on the cell surface is tightly regulated and abnormal appearance is associated with a number of inflammatory disease conditions. Multiple studies indicate that the selectins mediate neutrophil, monocyte, and lymphocyte rolling along the venular wall.

A long-standing enigma has been the role of N-linked glycans attached to many proteins in the endoplasmic reticulum (ER) and their co- and posttranslational remodelling along the secretory pathway. Evidence is accumulating that intracellular animal lectins play important roles in quality control and glycoprotein sorting along the secretory pathway. Calnexin and calreticulin in conjunction with associated chaperones promote correct folding and oligomerization of many glycoproteins in the ER. The discovery that one of these glycan modifications, mannose 6-phosphate, serves as a lysosomal targeting signal that is recognized by mannose 6-phosphate receptors has led to the notion that lectins may play more general roles in exocytotic protein trafficking ( Chaps. 3– 6). In present and subsequent chapters we discuss the role of intracellular lectins in quality control and their role in understanding the mechanisms underlying protein traffic in the secretory pathway ( Chaps. 3– 7) (Table 2.1).