the human 2 m shows 70% amino acid sequence similarity to the murine protein and both of them locate on the syntenic chromosomes . the secondary structure of 2 m consists of seven -strands which are organized into two -sheets linked by a single disulfide bridge , presenting a classical -sandwich typical of the immunoglobulin ( ig ) domain . 2 m has no transmembrane region and contains a distinctive molecular structure called a constant-1 ig superfamily domain , sharing with other adaptive immune molecules including major histocompatibility complex ( mhc ) class i and class ii . two evolutionary conserved tryptophan ( trp ) residues are important for correct structural fold and function of 2 m . trp60 is exposed to the solvent at the apex of a protein loop and is critical for promoting the association of 2 m in mhc i. the mutation of trp60 increases the stabilization of 2 m , inhibits 2 amyloidogenic propensity , and weakens the interaction with the heavy chain of mhc i. trp95 is buried in the 2 m core , and the mutation of trp95 destabilizes the protein , yielding nonfibrillar 2 m aggregates . both trp residues play differential and complementary roles in the structure of 2 m , distinctly affecting 2 m toward self - aggregation into amyloid fibrils . once the aspartate residue is replaced by asparagine residue at position 76 , 2 m becomes thermodynamically unstable and remarkably fibrillogenic in vitro under physiological conditions . normally , 2 m is noncovalently linked with the other polypeptide chain (  chain ) to form mhc i or like structures , including mhc i , neonatal fc receptor ( fcrn ) , a cluster of differentiation 1 ( cd1 ) , human hemochromatosis protein ( hfe ) , qa , and so on . thus , the conformation of  chain is highly dependent on the presence of 2 m . although 1 and 2 domains differ among molecules , 3 domain and 2 m are relatively conserved , where the intermolecular interaction occurs . a number of residues at the points of contact with 2 m are shared among mhc i or like molecules . furthermore , interactions with 1 and 2 domains are important for the paired association of 3 domain and 2 m in the presence of native antigens . 2 m could dissociate from such molecules and shed into the serum , where it is transported to the kidneys to be degraded and excreted . an 88-kd protein ( calnexin ) associates rapidly and quantitatively with newly synthesized murine mhc i molecules within the endoplasmic reticulum . both 2 m and peptide not only 2 m is to interact with and stabilize the tertiary structure of the mhc i or like molecules , but also it is extensively involved in the functional regulation of survival , proliferation , apoptosis , and even metastasis in cancer cells . as well as a cancer prognostic marker , although 2 m acts as both a positive and negative growth factor in different cancer cells , the application of anti-2 m antibodies induces cancer cell apoptosis and do not block the down - regulation effect of 2 m in myeloma cells . moreover , systemic 2 m accumulation in aging blood promoted age - related cognitive dysfunction and impairs neurogenesis , suggesting that 2 m may be targeted therapeutically in old age . thus , targeting 2 m will shed light on the modulatory activity in the immune system and provide new pathways on cancer or aging - related therapeutics . this review will only focus on the characteristic and function of 2 m under present knowledge . for mhc i or like molecules , they have been well reviewed previously and are not the scope of this study . 2 m expresses at a constant level in many cells , however , the formation of 2 m would be enhanced in the presence of ifn-. 2 m could induce the expression of interleukin 6 ( il-6 ) , 8 and 10 in several cell types , regulate the expression of hormone / growth factor , and coordinate the interaction between cytokines and their receptors . like a prototypical oncogenic factor , 2 m is able to stimulate growth and progression of various cancers . in cancer bone metastasis , 2 m allows cancer cells to continue to synthesize and deposit bone - like proteins . the growth and migration of mesenchymal stem cells would be promoted by exogenous overexpression of 2 m through enhanced phosphorylation of camp response element - binding protein and upregulation of il-6 and vascular endothelial growth factor . 2 m could support lethal bone and soft tissue metastasis via activating epithelial to mesenchymal transition . 2 m also acts as an apoptosis - inducing factor in several leukemic , lymphoma , and myeloma cell lines . inhibition of 2 m enhanced the radiation sensitivity by induction of iron overload in prostate cancer cells . in patients suffering from long - term hemodialysis , a high concentration of serum 2 m leads that 2 m deposits in skeletal joints and forms amyloid plaques . among the fibrils , full - length 2 m is the major component , although other derivatives of 2 m are also present . furthermore , the h51a point mutation of 2 m exhibits a 2-fold increase in the lag - time of fibril formation . 2 m also induces a dose- and time - dependent , cell - mediated calcium efflux from neonatal mouse calvariae that involves osteoclast stimulation , which is mediated by il-1 partly . the expression and covalent association of tapasin , assisting mhc i to load antigenic peptides , were enhanced by the presence of 2 m . the abnormal level of 2 m in blood or urea is associated with multiple diseases , such as some acute and chronic inflammations , liver or renal dysfunctions , some viral infections , and several malignancies . furthermore , amyloidosis associated to hemodialysis is related with persistently high 2 m serum levels . in rare cases , a cerebrospinal fluid 2 m level is used to assess a disease involved with the central nervous system . serum and plasma 2 m values reflect the activation of the cellular immune system , as well as a tumor marker in certain hematologic malignancies . for the inflammatory bowel disease , m levels also rise during infection with some viruses , including cytomegalovirus and human immunodeficiency virus ( hiv ) . recently , soluble 2 m was proposed as a possible serologic marker of neurologic disease during the infection of human t - cell leukemia virus . on the other hand , abnormality of urine 2 m values indicates renal filtration or reabsorption disorders . the small size of 2 m allows it pass through the glomerular membrane , however , it can be reabsorbed in the proximal tubules by specific receptors . the disorder of kidney 's glomeruli would cause increased 2 m in blood and decreased 2 m in urea , in contrast , the disorder of kidney 's tubules would cause increased 2 m in urea and decreased 2 m in blood . in lupus nephritis and neonates , the index of serum 2m / cystatin c is suggested to indicate the renal function . moreover , serum 2 m levels at discharge would predict the long - term mortality and graft loss in kidney transplantation recipients . a large nationally representative cohort exhibited serum 2 m concentration was associated with a significantly increased risk of cardiovascular and all - cause mortality . recently , the concentration of 2 m was also deemed as a marker of frailty in older people . thus , the 2 m test could indicate how advanced the disease is and the likely prognosis for the patient at the time of diagnosis . 2 m deficient mutant has been derived in different models and changes of cellular and humoral responses are evaluated in these 2 m deficient animals . the mechanism of mhc i presenting peptides to cd8 t - cell was shown in figure 1 . due to the lack of 2 m determined mhc i molecules , the number of cd8 t - cells significantly decreases in 2 m deficient mice . therefore , the deficient mice are susceptible to intracellular pathogens , including listeria monocytogenes , mycobacterium tuberculosis , influenza virus , and so on . however , 2 m deficient mice could generate cd4 mhc ii - restricted cytotoxic t - cells ( ctl ) following infection with sendai virus or lymphocytic choriomeningitis virus . furthermore , mhc i - restricted ctl activity could be activated during infections by some specific pathogens even in 2 m deficient mice . in 2 m deficient mice , natural killer cells are shown with increased sensitivity to mhc i heavy chain mediated inhibition . other cellular responses are relatively stable , including gamma delta+ t - cells and cd4 t - cells . the catabolism of igg and albumin increased in 2 m deficient mice due to low expression of fcrn . however , the level of mucosal iga was significantly increased during enteric infection of 2 m deficient mice , indicating different roles of 2 m in ig catabolism . on the other hand , autoantibody - mediated inflammations or immune diseases are prevented or relieved in 2 m deficient mice . the disruption of 2 m significantly reduced the expression of mhc i in human embryonic stem cells , presenting hypoimmunogenic and favoring transplantation therapies . mhc i consists of two polypeptide chains ,  ( 1 , 2 , 3 ) and 2 m , which are noncovalently linked between 3 and 2 m . the peptides ( antigens ) generated from cytosolic proteins bind the polymorphic groove between 1 and 2 and are displayed to cd8 t - cell receptors . meanwhile , 2 m : beta 2 microglobulin ; mhc i : major histocompatibility complex class i ; cd8 : cluster of differentiation 8 . the main function of mhc i or mhc i - like molecules is related with molecular presentations or uptakes , depending on the structural - like grooves between 1 and 2 domains . comparing with mhc i groove , the cd1 groove is relatively narrow , deep , and highly hydrophobic forming two deep binding pockets . cd1 molecules are targeted to distinct endocytic compartments by cytoplasmic tails . on the other hand , although these structures are highly similar , different functions are presented with these molecules relating to site mutagenesis on specific binding sites . the most striking difference of fcrn is the closing of the groove that binds peptides in classical mhc i proteins , due to a kink in the 2 helix introduced by proline ( pro)-162 . moreover , the pocket of fcrn is blocked by the positively charged side chain of arginine ( arg)-164 . 2 m stabilizes the tertiary structure of such heterodimers and also participates in the selections of mhc i - like restricted t - cells . for instance , the selection of invariant v19-j33 cells is dependent on 2 m . mhc i molecules are found on nearly every nucleated cell of the body . their function is to present short endogenous or exogenous peptides from within the cell to ctls . 2 m is crucial to stabilize cell surface mhc i , keep native structure of mhc i heavy chain , facilitate the binding of antigenic peptides , and generate additional high - affinity peptide - bindings . however , some cells express a considerable number of surface mhc i heavy chain molecules not associated with 2 m . the superficial nonpeptide - associated heavy chains can associate with exogenously provided 2 m and synthetic peptide antigens . moreover , normal 2m - sufficient cells grown in serum - free media devoid of 2 m also require an exogenous 2 m to efficiently bind synthetic peptide . by using this characteristic , 2 m was developed to vaccine adjuvant for ctl activation . using the immunization protocol with human 2 m , ctl responses were strongly primed with peptides from ova , s. virus , and vesicular stomatitis virus in mice . the versatility of 2 m in different species confirms the conservative evolutionary lineage of this small protein . esat-6 , an abundantly secreted protein of m. tuberculosis , could directly interact with human 2 m to inhibit the expression of mhc i , resulting in down - regulation of class i - mediated antigen presentation . both proteins are protected by fcrn from lysosomal degradation and extend the catabolic half - lives . beside the protection role with fcrn heterodimer , 2 m seems to have another way to protect the degradation of igg and albumin . furthermore , fcrn is critically involved in the transport of igg across cells , thus helping antigen delivery via transcytosis . 2 m is critical for surface expression of fcrn , facilitating fcrn to exit the endoplasmic reticulum . furthermore , 2 m is important for efficient ph - dependent binding of igg by fcrn . not only overexpression of fcrn enhances the transcytosis of immune complexes and increases the number of antigen - specific igm or igg - producing b cells , but also the expression of 2 m increases the transcytosis of igg between the basolateral and apical directions of epithelial cells . moreover , the application of 2 m as adjuvant requires the temporal proximity with antigens , confirming that 2 m facilitates the uptake of antigens . cd1 is a family of glycoproteins expressed on the surface of various antigen - presenting cells , and cd1-like genes have been found in many vertebrate genomes . they are closely related to the mhc i and are involved in the presentation of lipid antigens to restricted t - cells . according to protein sequence homologies , group 1 cd1 includes cd1a , -b , and -c and human , mouse , rat , and rabbit cd1d form group ii . furthermore , cd1e is proposed to form a third group due to its intracellular chaperone function . the size and shape of the antigen - binding groove vary among different cd1 isoforms and decide the nature of the binding lipid molecules . for instance , heavy chains of cd1b are detained in the er in 2m - deficient cells , however , a portion of cd1d heavy chains can exit the er and reach the cell surface independent on2 m . interestingly , the non-2 m formed cd1d only presents at the apical site of intestinal epithelial cells . like the adjuvant application of 2 m on ctl , 2 m seems like a potential adjuvant to prime cd1d specific immune responses . as an mhc i - like molecule , hfe is a ligand for the transferrin receptor , regulating the uptake of iron - bound transferrin . hepcidin regulated by hfe degrades the iron transporter ferroportin on the cytoplasmic membrane of enterocytes and macrophages , resulting in decreased iron uptake from food and iron release from recycled red blood cells . therefore , mutations of hfe or absence of 2 m result in iron excess and hemochromatosis . the mechanism of iron accumulation in the 2 m deficient mouse may be more complex than only involving hfe . in contrast to hfe  chain - deficient mice , 2m - deficient mice display increased levels of iron transporters and iron overload , suggesting that ( an ) additional 2 m interacting protein(s ) could be involved in controlling iron homeostasis . the interaction with 2 m is crucial for surface expression of hfe . unlike other mhc i - like molecules their function is to present short endogenous or exogenous peptides from within the cell to ctls . 2 m is crucial to stabilize cell surface mhc i , keep native structure of mhc i heavy chain , facilitate the binding of antigenic peptides , and generate additional high - affinity peptide - bindings . however , some cells express a considerable number of surface mhc i heavy chain molecules not associated with 2 m . the superficial nonpeptide - associated heavy chains can associate with exogenously provided 2 m and synthetic peptide antigens . moreover , normal 2m - sufficient cells grown in serum - free media devoid of 2 m also require an exogenous 2 m to efficiently bind synthetic peptide . by using this characteristic , 2 m was developed to vaccine adjuvant for ctl activation . using the immunization protocol with human 2 m , ctl responses were strongly primed with peptides from ova , s. virus , and vesicular stomatitis virus in mice . the versatility of 2 m in different species confirms the conservative evolutionary lineage of this small protein . esat-6 , an abundantly secreted protein of m. tuberculosis , could directly interact with human 2 m to inhibit the expression of mhc i , resulting in down - regulation of class i - mediated antigen presentation . both proteins are protected by fcrn from lysosomal degradation and extend the catabolic half - lives . beside the protection role with fcrn heterodimer , 2 m seems to have another way to protect the degradation of igg and albumin . furthermore , fcrn is critically involved in the transport of igg across cells , thus helping antigen delivery via transcytosis . 2 m is critical for surface expression of fcrn , facilitating fcrn to exit the endoplasmic reticulum . furthermore , 2 m is important for efficient ph - dependent binding of igg by fcrn . not only overexpression of fcrn enhances the transcytosis of immune complexes and increases the number of antigen - specific igm or igg - producing b cells , but also the expression of 2 m increases the transcytosis of igg between the basolateral and apical directions of epithelial cells . moreover , the application of 2 m as adjuvant requires the temporal proximity with antigens , confirming that 2 m facilitates the uptake of antigens . cd1 is a family of glycoproteins expressed on the surface of various antigen - presenting cells , and cd1-like genes have been found in many vertebrate genomes . they are closely related to the mhc i and are involved in the presentation of lipid antigens to restricted t - cells . according to protein sequence homologies , group 1 cd1 includes cd1a , -b , and -c and human , mouse , rat , and rabbit cd1d form group ii . furthermore , cd1e is proposed to form a third group due to its intracellular chaperone function . the size and shape of the antigen - binding groove vary among different cd1 isoforms and decide the nature of the binding lipid molecules . for instance , heavy chains of cd1b are detained in the er in 2m - deficient cells , however , a portion of cd1d heavy chains can exit the er and reach the cell surface independent on2 m . interestingly , the non-2 m formed cd1d only presents at the apical site of intestinal epithelial cells . like the adjuvant application of 2 m on ctl , 2 m seems like a potential adjuvant to prime cd1d specific immune responses . as an mhc i - like molecule , hfe is a ligand for the transferrin receptor , regulating the uptake of iron - bound transferrin . hepcidin regulated by hfe degrades the iron transporter ferroportin on the cytoplasmic membrane of enterocytes and macrophages , resulting in decreased iron uptake from food and iron release from recycled red blood cells . therefore , mutations of hfe or absence of 2 m result in iron excess and hemochromatosis . the mechanism of iron accumulation in the 2 m deficient mouse may be more complex than only involving hfe . in contrast to hfe  chain - deficient mice , 2m - deficient mice display increased levels of iron transporters and iron overload , suggesting that ( an ) additional 2 m interacting protein(s ) could be involved in controlling iron homeostasis . the interaction with 2 m is crucial for surface expression of hfe . unlike other mhc i - like molecules qa-1 ( hla - e , human functional counterpart ) is designated as nonclassical histocompatibility ags , eliciting strong ctl responses . 2 m is required for an initial folding of qa-1 , however , transporter associated with antigen processing ( tap ) is not necessary for processing of qa-1 molecules . furthermore , the presence of cd8/ tcr/ cells in intestinal intraepithelial lymphocytes is highly restricted by qa-2 ( hla - g , human functional counterpart ) . histocompatibility 2 , m region locus 3 ( h2-m3 ) associates with 2 m to form mhc i - like structure . h2-m3 mainly presents n - formylated peptides , and its surficial expression is dependent on ligand binding . once h2-m3 binds peptides in the endoplasmic reticulum , they transit rapidly to the cell surface , where they stimulate cd8  t - cells in a tap - dependent manner . human mr1 encoded on chromosome 1 is highly conserved among mammals and is more closely related to classical class i molecules than are other nonclassical class i family members . the mr1 is responsible for activation of mucosal - associated invariant t - cells expressing semi - invariant t - cell receptors in the presence of bacteria . moreover , the mr1 messenger rna is ubiquitously expressed in different tissues or cell lines and the surficial expression of mr1 requires the presence of 2 m . the lack of 2 m or mr1 increases the susceptibility to infection by klebsiella pneumoniae . mill ( mhc class i - like located near the leukocyte receptor complex ) is a family of mhc i - like molecules , which are glycophosphatidylinositol - anchored glycoproteins associated with 2 m . surface expression of mill does not require functional tap molecules and is not related with the presentation of peptides . given the structural similarities , it is believed that all these mhc i or mhc i - like molecules have evolutionary lineage with a common ancestor . the mhc locus has been found in all jawed vertebrates , however , the proto - mhc could trace back to the cephalochordate ( amphioxus ) and jawless vertebrate lineages . mhc ii genes were firstly derived from proto - mhc by exon shuffling , combining an ig - like c domain with a peptide binding region . subsequently , another peptide binding region exon was added to mhc ii  chain to form the mhc i heavy chain , which happened at approximately 500 million years ago . the emergence of cd1 occurred in the reptile form lineage after the amphibian  reptile split roughly between 365 and 385 million years ago . contrasting to positive selection on the ligand - binding site of mhc i , the conservative ligand - binding site of mr1 evolved under strong negative selection . fcrn is supposed to share an ancestor with the mhcs that it does not with the cd1s . further evidence shows , fcrn diverged from the mhc near the most recent common ancestor of lizards and mammals . the close proximity of mhc i , mhc ii , and 2 m implies that they were derived from a common ancestor by tandem ( cis ) duplication . 2 m protein sequences are highly conserved among species , and overall structures are virtually identical . ten residues are identical in all species , including the two characteristically spaced cysteine residues which form the disulfide bridge . the structure and function are highly conserved not only in 2 m but also in its related molecules . m involves in the network of cytokines , modulating the development of several cell lines . furthermore , hormone , growth factors , and cognate receptors are also regulated by 2 m . as a prognostic marker of various diseases , the level of 2 m reflects the progress of the disease and the likely prognosis for the patient . the special role of 2 m in regulating the survival , proliferation , apoptosis , and even metastasis of cancer cells makes itself being targeted for cancer therapeutics [ table 1 ] . examples of multifunction of 2 m mhc i : major histocompatibility complex class i ; il : interleukin ; creb : camp response element - binding ; vegf : vascular endothelial growth factor ; 2 m : beta 2 microglobulin ; igf - i : insulin - like growth factor - i ; camp : cyclic adenosine monophosphate . as a key component of mhc i or like molecules , the ctl immune response is obligatory for prevention against intracellular pathogens . by use of mhc i  chain , 2 m has been successfully employed as an adjuvant for augmented ctl immune responses . due to the surface expression of other mhc i - like  chains ( e.g. , cd1d  chain ) , it can be deduced the application of 2 m on additive immune responses . since mhc i and cd1 could present different antigens from m. tuberculosis to cd8 t - cells ; the adjuvant effect of 2 m may have dual applications on prevention of tuberculosis . though several 2m - related molecules have been identified , there are still some unknown 2m - related molecules . besides fcrn and hfe , other 2m - related molecules involve in the catabolism of igg and the homeostasis of iron . with the sequences of the whole genomes , this study was funded by the grant from the national nature science foundation of china ( no . this study was funded by the grant from the national nature science foundation of china ( no .
objective : this review focuses on the current knowledge on the implication and significance of beta 2 microglobulin ( 2 m ) , a conservative immune molecule in vertebrate.data sources : the data used in this review were obtained from pubmed up to october 2015 . terms of 2 m , immune response , and infection were used in the search.study selections : articles related to 2 m were retrieved and reviewed . 
 articles focusing on the characteristic and function of 2 m were selected . 
 the exclusion criteria of articles were that the studies on 2m - related molecules.results:2m is critical for the immune surveillance and modulation in vertebrate animals . 
 the dysregulation of 2 m is associated with multiple diseases , including endogenous and infectious diseases . 
 2 m could directly participate in the development of cancer cells , and the level of 2 m is deemed as a prognostic marker for several malignancies . 
 it also involves in forming major histocompatibility complex ( mhc class i or mhc i ) or like heterodimers , covering from antigen presentation to immune homeostasis.conclusions:based on the characteristic of 2 m , it or its signaling pathway has been targeted as biomedical or therapeutic tools . 
 moreover , 2 m is highly conserved among different species , and overall structures are virtually identical , implying the versatility of 2 m on applications .