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Review Article

The Implication and Significance of Beta 2 Microglobulin:


AConservative Multifunctional Regulator
Ling Li1,2, Mei Dong3, XiaoGuang Wang4
Department of Food Quality and Safety, College of Food Science and Biotechnology, Tianjin Agricultural University, Tianjin 300384, China
1

2
Tianjin Engineering Research Center of Agricultural Products Processing, Tianjin 300384, China
3
Department of Clinical Laboratory, Wangdu Hospital of Traditional Chinese Medicine, Baoding, Hebei 072450, China
4
Department of Immunology and Microbiology, Anschutz Medical Campus, University of Colorado Denver, Aurora 80045, Colorado, USA

Abstract
Objective: This review focuses on the current knowledge on the implication and significance of beta 2 microglobulin(2M), a conservative
immune molecule in vertebrate.
Data Sources: The data used in this review were obtained from PubMed up to October 2015. Terms of 2M, immune response, and
infection were used in the search.
Study Selections: Articles related to 2M were retrieved and reviewed. Articles focusing on the characteristic and function of 2M were
selected. The exclusion criteria of articles were that the studies on 2Mrelated molecules.
Results: 2M is critical for the immune surveillance and modulation in vertebrate animals. The dysregulation of 2M is associated
with multiple diseases, including endogenous and infectious diseases. 2M could directly participate in the development of cancer cells,
and the level of 2M is deemed as a prognostic marker for several malignancies. It also involves in forming major histocompatibility
complex(MHC classI or MHC I) or like heterodimers, covering from antigen presentation to immune homeostasis.
Conclusions: Based on the characteristic of 2M, it or its signaling pathway has been targeted as biomedical or therapeutic tools.
Moreover, 2M is highly conserved among different species, and overall structures are virtually identical, implying the versatility of
2M on applications.

Key words: Beta 2 Microglobulin; Immune Dysregulation; Major Histocompatibility Complex ClassI or Like Molecules

Introduction residues are important for correct structural fold and function
of 2M.[3,9] Trp60 is exposed to the solvent at the apex of a
Beta 2 microglobulin(2M) is a small protein (11,800
protein loop and is critical for promoting the association
Dalton), presenting in nearly all nucleated cells and most
of 2M in MHC I. The mutation of Trp60 increases the
biological fluids, including serum, urine, and synovial
stabilization of 2M, inhibits 2 amyloidogenic propensity,
fluid.[1,2] No genetic variant of 2M is known in human.[3]
and weakens the interaction with the heavy chain of MHC I.
The human 2M shows 70% amino acid sequence similarity
Trp95 is buried in the 2M core, and the mutation of Trp95
to the murine protein and both of them locate on the syntenic
destabilizes the protein, yielding nonfibrillar 2M aggregates.
chromosomes.[1,4] The secondary structure of 2M consists
Both Trp residues play differential and complementary roles
of seven strands which are organized into two sheets
linked by a single disulfide bridge, presenting a classical
Address for correspondence: Dr.XiaoGuang Wang,
sandwich typical of the immunoglobulin(Ig) domain.[57] Department of Immunology and Microbiology, University of Colorado
2M has no transmembrane region and contains a distinctive Denver, Anschutz Medical Campus, Aurora 80045, Colorado, USA
molecular structure called a constant1 Ig superfamily EMail:wxg402@hotmail.com
domain, sharing with other adaptive immune molecules
including major histocompatibility complex(MHC) classI This is an open access article distributed under the terms of the Creative Commons
and classII.[8] Two evolutionary conserved tryptophan (Trp) AttributionNonCommercialShareAlike 3.0 License, which allows others to remix,
tweak, and build upon the work noncommercially, as long as the author is credited
Access this article online and the new creations are licensed under the identical terms.

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Received: 03112015 Edited by: Peng Lyu


DOI: How to cite this article: Li L, Dong M, Wang XG. The Implication and
10.4103/0366-6999.176084 Significance of Beta 2 Microglobulin: A Conservative Multifunctional
Regulator. Chin Med J 2016;129:448-55.

448 Chinese Medical Journal February 20, 2016 Volume 129 Issue 4
in the structure of 2M, distinctly affecting 2M toward cancer bone metastasis, 2M allows cancer cells to continue
selfaggregation into amyloid fibrils. Once the aspartate to synthesize and deposit bonelike proteins. The growth and
residue is replaced by asparagine residue at position 76, migration of mesenchymal stem cells would be promoted
2M becomes thermodynamically unstable and remarkably by exogenous overexpression of 2M through enhanced
fibrillogenic invitro under physiological conditions.[10] phosphorylation of cAMP response elementbinding
protein and upregulation of IL6 and vascular endothelial
Normally, 2M is noncovalently linked with the other
growth factor.[26,27] 2M could support lethal bone and soft
polypeptide chain( chain) to form MHC I or like structures,
tissue metastasis via activating epithelial to mesenchymal
including MHC I, neonatal Fc receptor(FcRn), a cluster of
transition.[28,29] 2M also acts as an apoptosisinducing
differentiation 1(CD1), human hemochromatosis protein(HFE),
factor in several leukemic, lymphoma, and myeloma cell
Qa, and so on. 2M makes extensive contacts with all three
lines.[18,30,31] Inhibition of 2M enhanced the radiation
domains of the chain.[11] Thus, the conformation of chain
sensitivity by induction of iron overload in prostate cancer
is highly dependent on the presence of 2M. Although 1 and
cells.[32]
2 domains differ among molecules, 3 domain and 2M
are relatively conserved, where the intermolecular interaction In patients suffering from longterm hemodialysis, a high
occurs.[12] A number of residues at the points of contact with 2M concentration of serum 2M leads that 2M deposits in
are shared among MHC I or like molecules.[13] Furthermore, skeletal joints and forms amyloid plaques. Among the
interactions with 1 and 2 domains are important for the paired fibrils, fulllength 2M is the major component, although
association of 3 domain and 2M in the presence of native other derivatives of 2M are also present.[33] Furthermore,
antigens.[14] 2M could dissociate from such molecules and the H51A point mutation of 2M exhibits a 2fold increase
shed into the serum, where it is transported to the kidneys to be in the lagtime of fibril formation.[34]
degraded and excreted. An 88kD protein(calnexin) associates
2M also induces a doseand timedependent, cellmediated
rapidly and quantitatively with newly synthesized murine MHC
calcium efflux from neonatal mouse calvariae that involves
I molecules within the endoplasmic reticulum.[15] Both 2M
osteoclast stimulation, which is mediated by IL1 partly.[35]
and peptide are required for efficient calnexin dissociation and
The expression and covalent association of tapasin, assisting
subsequent MHC I transport.[16]
MHC I to load antigenic peptides, were enhanced by the
Not only 2M is to interact with and stabilize the tertiary presence of 2M.[36]
structure of the MHC I or like molecules, but also it is
extensively involved in the functional regulation of survival, Indications from the Level of Free Beta 2
proliferation, apoptosis, and even metastasis in cancer
cells.[17] As well as a cancer prognostic marker, 2M is also Microglobulin
a promising cancer therapeutic target. Although 2M acts The abnormal level of 2M in blood or urea is associated
as both a positive and negative growth factor in different with multiple diseases, such as some acute and chronic
cancer cells, the application of anti2M antibodies induces inflammations, liver or renal dysfunctions, some viral
cancer cell apoptosis and do not block the downregulation infections, and several malignancies. [2,17] Furthermore,
effect of 2M in myeloma cells.[18] Moreover, systemic 2M amyloidosis associated to hemodialysis is related with
accumulation in aging blood promoted agerelated cognitive persistently high 2M serum levels.[3739] In rare cases, a
dysfunction and impairs neurogenesis, suggesting that 2M cerebrospinal fluid 2M level is used to assess a disease
may be targeted therapeutically in old age.[19] Thus, targeting involved with the central nervous system.[40,41]
2M will shed light on the modulatory activity in the immune
Serum and plasma 2M values reflect the activation of
system and provide new pathways on cancer or agingrelated
the cellular immune system, as well as a tumor marker in
therapeutics. This review will only focus on the characteristic
certain hematologic malignancies.[4247] For the inflammatory
and function of 2M under present knowledge. For MHC I
bowel disease, 2M was suggested to be used as an activity
or like molecules, they have been well reviewed previously
parameter.[48] 2M levels also rise during infection with
and are not the scope of this study.
some viruses, including cytomegalovirus and human
immunodeficiency virus(HIV).[49] Strong evidence showed
Regulation and Modulation of Beta 2 cytomegalovirus could directly bind 2M via two envelope
Microglobulin proteins.[50] Recently, soluble 2M was proposed as a possible
serologic marker of neurologic disease during the infection
2M expresses at a constant level in many cells, however,
of human Tcell leukemia virus.[51] On the other hand,
the formation of 2M would be enhanced in the presence of
abnormality of urine 2M values indicates renal filtration
IFN.[17] 2M could induce the expression of interleukin
or reabsorption disorders. The small size of 2M allows it
6(IL6), 8 and 10 in several cell types, regulate the
pass through the glomerular membrane, however, it can be
expression of hormone/growth factor, and coordinate the
reabsorbed in the proximal tubules by specific receptors.
interaction between cytokines and their receptors.[2022]
The disorder of kidneys glomeruli would cause increased
Like a prototypical oncogenic factor, 2M is able to 2M in blood and decreased 2M in urea, in contrast, the
stimulate growth and progression of various cancers.[2325] In disorder of kidneys tubules would cause increased 2M in

Chinese Medical JournalFebruary 20, 2016Volume 129Issue 4 449


urea and decreased 2M in blood.[2] In lupus nephritis and responses are relatively stable, including gamma delta+
neonates, the index of serum 2M/cystatin C is suggested Tcells and CD4+Tcells.[67] Hemochromatosis is evident
to indicate the renal function.[52,53] Moreover, serum 2M in 2M deficient mice, presenting iron overload.[62] The
levels at discharge would predict the longterm mortality iron overload increases the sensitivity to the infection of
and graft loss in kidney transplantation recipients.[54] A M.tuberculosis.[61] The catabolism of IgG and albumin
large nationally representative cohort exhibited serum 2M increased in 2M deficient mice due to low expression
concentration was associated with a significantly increased of FcRn.[68,69] However, the level of mucosal IgA was
risk of cardiovascular and allcause mortality.[55] Recently, significantly increased during enteric infection of 2M
the concentration of 2M was also deemed as a marker of deficient mice, indicating different roles of 2M in Ig
frailty in older people.[56] Thus, the 2M test could indicate catabolism. On the other hand, autoantibodymediated
how advanced the disease is and the likely prognosis for the inflammations or immune diseases are prevented or
patient at the time of diagnosis. relieved in 2M deficient mice.[70,71] The disruption of 2M
significantly reduced the expression of MHC I in human
embryonic stem cells, presenting hypoimmunogenic and
Outcomes Due to Beta 2 Microglobulin favoring transplantation therapies.[72] Furthermore, the loss
Deficiency of 2M contributes the immune evasion in cancer cells.[73]
2M deficient mutant has been derived in different
models and changes of cellular and humoral responses Specific Roles of Beta 2 Microglobulin Within
are evaluated in these 2M deficient animals. [57] The
mechanism of MHC I presenting peptides to CD8+Tcell Heterodimers
was shown in Figure1. Due to the lack of 2M determined The main function of MHC I or MHC Ilike molecules
MHC I molecules, the number of CD8+Tcells significantly is related with molecular presentations or uptakes,
decreases in 2M deficient mice. [5862] Therefore, the depending on the structurallike grooves between 1 and
deficient mice are susceptible to intracellular pathogens, 2 domains. Comparing with MHC I groove, the CD1
including Listeria monocytogenes, Mycobacterium groove is relatively narrow, deep, and highly hydrophobic
tuberculosis, influenza virus, and so on. However, 2M forming two deep binding pockets.[74,75] This hydrophobic
deficient mice could generate CD4+MHC IIrestricted channel is specific for binding hydrocarbon alkyl chains.
cytotoxic Tcells(CTL) following infection with Sendai Unlike MHC I, CD1 molecules are targeted to distinct
virus or lymphocytic choriomeningitis virus. [63,64] endocytic compartments by cytoplasmic tails. On the
Furthermore, MHC Irestricted CTL activity could be other hand, the FcRn groove is collapsed, demonstrating
activated during infections by some specific pathogens a relatively flat groove. Although these structures are
even in 2M deficient mice.[65] In 2M deficient mice, highly similar, different functions are presented with
natural killer cells are shown with increased sensitivity to these molecules relating to site mutagenesis on specific
MHC I heavy chain mediated inhibition.[66] Other cellular 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.[13] Moreover, the pocket of FcRn is
blocked by the positively charged side chain of arginine
(Arg)164. 2M stabilizes the tertiary structure of such
heterodimers and also participates in the selections of
MHC Ilike restricted Tcells. For instance, the selection
of invariant V19J33+cells is dependent on 2M.[76]
Major histocompatibility complex classI
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. 2M 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
highaffinity peptidebindings.[77] However, some cells
Figure1: Schematic representation of MHC I antigen presentation to express a considerable number of surface MHC I heavy
CD8 Tcell. MHC I consists of two polypeptide chains, (1, 2,
chain molecules not associated with 2M. [14,78,79] The
3) and 2M, which are noncovalently linked between 3 and 2M.
The peptides(antigens) generated from cytosolic proteins bind the
superficial nonpeptideassociated heavy chains can
polymorphic groove between 1 and 2 and are displayed to CD8 Tcell associate with exogenously provided 2M and synthetic
receptors. Meanwhile, the CD8 coreceptor of CD8 Tcell would interact peptide antigens.[80] Moreover, normal 2Msufficient cells
with 3. 2M: Beta 2 microglobulin; MHC I: Major histocompatibility grown in serumfree media devoid of 2M also require an
complex classI; CD8: Cluster of differentiation 8. exogenous 2M to efficiently bind synthetic peptide. By

450 Chinese Medical Journal February 20, 2016 Volume 129 Issue 4
using this characteristic, 2M was developed to vaccine intestinal epithelial cells.[96] Like the adjuvant application of
adjuvant for CTL activation.[81] Using the immunization 2M on CTL, 2M seems like a potential adjuvant to prime
protocol with human 2M, CTL responses were strongly CD1d specific immune responses.
primed with peptides from OVA, S.virus, and vesicular
stomatitis virus in mice. The versatility of 2M in
Human hemochromatosis protein
As an MHC Ilike molecule, HFE is a ligand for the
different species confirms the conservative evolutionary
transferrin receptor, regulating the uptake of ironbound
lineage of this small protein. ESAT6, an abundantly
secreted protein of M.tuberculosis, could directly interact transferrin. Hepcidin regulated by HFE degrades the iron
with human 2M to inhibit the expression of MHC I, transporter ferroportin on the cytoplasmic membrane of
resulting in downregulation of classImediated antigen enterocytes and macrophages, resulting in decreased iron
presentation.[82] uptake from food and iron release from recycled red blood
cells. Therefore, mutations of HFE or absence of 2M result
Neonatal Fc receptor in iron excess and hemochromatosis.[5961] The mechanism
FcRn is a heterodimer of a nonclassical MHC I alpha of iron accumulation in the 2M deficient mouse may be
chain and 2M. It efficiently binds the two most abundant more complex than only involving HFE.[62] In contrast to
serum proteins, IgG, and albumin. Both proteins are HFE chaindeficient mice, 2Mdeficient mice display
protected by FcRn from lysosomal degradation and increased levels of iron transporters and iron overload,
extend the catabolic halflives.[69] Beside the protection suggesting that(an) additional 2M interacting protein(s)
role with FcRn heterodimer, 2M seems to have another could be involved in controlling iron homeostasis. The
way to protect the degradation of IgG and albumin.[83] interaction with 2M is crucial for surface expression of
Furthermore, FcRn is critically involved in the transport HFE.[97,98] Unlike other MHC Ilike molecules, HFE does
of IgG across cells, thus helping antigen delivery via not bind any antigen.[99]
transcytosis.[84]
2M is critical for surface expression of FcRn, facilitating Other Major Histocompatibility Complex Ilike
FcRn to exit the endoplasmic reticulum.[85] Furthermore,
2M is important for efficient pHdependent binding of IgG
Molecules
by FcRn. Strong evidence show 2M could directly contact Qa1(HLAE, human functional counterpart) is designated
IgG ligand.[86] Not only overexpression of FcRn enhances as nonclassical histocompatibility Ags, eliciting strong
the transcytosis of immune complexes and increases CTL responses.[100] 2M is required for an initial folding
the number of antigenspecific IgM or IgGproducing of Qa1, however, transporter associated with antigen
B cells,[87] but also the expression of 2M increases the processing(TAP) is not necessary for processing of
transcytosis of IgG between the basolateral and apical Qa1 molecules. Furthermore, the presence of CD8/
directions of epithelial cells.[88] Moreover, the application TCR/ cells in intestinal intraepithelial lymphocytes
of 2M as adjuvant requires the temporal proximity with is highly restricted by Qa2(HLAG, human functional
antigens, confirming that 2M facilitates the uptake of counterpart).[101]
antigens.[81] Histocompatibility 2, M region locus 3(H2M3)
Cluster of differentiation 1 associates with 2M to form MHC Ilike structure.
CD1 is a family of glycoproteins expressed on the surface of The expression of H2M3 is confined to murid species,
various antigenpresenting cells, and CD1like genes have which are highly conserved. H2M3 mainly presents
been found in many vertebrate genomes. They are closely Nformylated peptides, and its surficial expression is
related to the MHC I and are involved in the presentation dependent on ligand binding. Once H2M3 binds peptides
of lipid antigens to restricted Tcells. According to protein in the endoplasmic reticulum, they transit rapidly to the
sequence homologies, the members of the CD1 family are cell surface, where they stimulate CD8+ Tcells in a
mainly divided into two groups.[89] Group1 CD1 includes TAPdependent manner.[102,103]
CD1a,b, andc and human, mouse, rat, and rabbit CD1d Human MR1 encoded on chromosome 1 is highly
form groupII. Furthermore, CD1e is proposed to form a third conserved among mammals and is more closely related
group due to its intracellular chaperone function.[90,91] The to classical classI molecules than are other nonclassical
size and shape of the antigenbinding groove vary among classI family members.[104,105] The MR1 is responsible for
different CD1 isoforms and decide the nature of the binding activation of mucosalassociated invariant Tcells expressing
lipid molecules. semiinvariant Tcell receptors in the presence of bacteria.
The excretion of different CD1 isoforms differs in the Moreover, the MR1 messenger RNA is ubiquitously
presence of 2M. For instance, heavy chains of CD1b are expressed in different tissues or cell lines[104], and the surficial
detained in the ER in 2Mdeficient cells,[92] however, a expression of MR1 requires the presence of 2M.[106] The
portion of CD1d heavy chains can exit the ER and reach lack of 2M or MR1 increases the susceptibility to infection
the cell surface independent on2M.[9395] Interestingly, the by Klebsiella pneumoniae.[107] MR1 is ideally suited to bind
non2M formed CD1d only presents at the apical site of ligands originating from vitamin metabolites.[108]

Chinese Medical JournalFebruary 20, 2016Volume 129Issue 4 451


MILL(MHC classIlike located near the leukocyte receptor ancestor by tandem(cis) duplication. [8] 2M protein
complex) is a family of MHC Ilike molecules, which sequences are highly conserved among species, and overall
are glycophosphatidylinositolanchored glycoproteins structures are virtually identical. Ten residues are identical
associated with 2M. Surface expression of MILL does not in all species, including the two characteristically spaced
require functional TAP molecules and is not related with the cysteine residues which form the disulfide bridge.[12]
presentation of peptides.[109]
Conclusion and Perspectives
Evolutionary Relationship among Major The structure and function are highly conserved not only
Histocompatibility Complex I or Like Molecules in 2M but also in its related molecules. It indicates that
Given the structural similarities, it is believed that all these 2M is irreplaceable in animals, especially in vertebrate.
MHC I or MHC Ilike molecules have evolutionary lineage 2M involves in the network of cytokines, modulating the
with a common ancestor.[13] The MHC locus has been found development of several cell lines. Furthermore, hormone,
in all jawed vertebrates, however, the protoMHC could growth factors, and cognate receptors are also regulated
trace back to the cephalochordate(amphioxus) and jawless by 2M. As a prognostic marker of various diseases, the
vertebrate lineages.[110112] MHC II genes were firstly derived level of 2M reflects the progress of the disease and the
from protoMHC by exon shuffling, combining an Iglike likely prognosis for the patient. The special role of 2M in
C domain with a peptide binding region.[113] Subsequently, regulating the survival, proliferation, apoptosis, and even
another peptide binding region exon was added to MHC II metastasis of cancer cells makes itself being targeted for
chain to form the MHC I heavy chain, which happened cancer therapeutics [Table 1].
at approximately 500 million years ago. The emergence As a key component of MHC I or like molecules, 2M is
of CD1 occurred in the reptile form lineage after the critical for CTL response. The CTL immune response is
amphibianreptile split roughly between 365 and 385 million obligatory for prevention against intracellular pathogens. By
years ago. The MR1 is highly conserved and seems to be use of MHC I chain, 2M has been successfully employed
unique to mammals.[114] Contrasting to positive selection as an adjuvant for augmented CTL immune responses.
on the ligandbinding site of MHC I, the conservative Due to the surface expression of other MHC Ilike
ligandbinding site of MR1 evolved under strong negative chains(e.g.,CD1d chain), it can be deduced the application
selection. H2M3 is also highly conserved, and its expression of 2M on additive immune responses. Since MHC I and
is confined to murid species. The emergence of H2M3 CD1 could present different antigens from M.tuberculosis
occurred 5065 million years ago.[114] FcRn is supposed to to CD8+Tcells; the adjuvant effect of 2M may have dual
share an ancestor with the MHCs that it does not with the applications on prevention of tuberculosis.
CD1s.[13] Further evidence shows, FcRn diverged from the
Though several 2Mrelated molecules have been identified,
MHC near the most recent common ancestor of lizards and
there are still some unknown 2Mrelated molecules.
mammals.
Besides FcRn and HFE, other 2Mrelated molecules
2M is believed to arise in a basal jawed vertebrate involve in the catabolism of IgG and the homeostasis of iron.
(gnathostome).[8] The close proximity of MHC I, MHC II, With the sequences of the whole genomes, more putative
and 2M implies that they were derived from a common 2Mrelated molecules would be revealed.[115]

Table1: Examples of multifunction of 2M


Year Author Targeting Mechanism Application
2007 Yang etal.[22] IL6 and IGFI receptors and Anti2M mAbs redistribute or block IL6 and Apoptosis of myeloma cells
signaling pathways IGFI receptors or signaling pathways
1995 Rowley etal.[25] Antagonistic activity to Hormone/growth factor receptors Immune regulation and cell
transforming growth factor beta 1 proliferation
2008 Zhu and Shi[27] Mesenchymal stem cells Growth stimulator Prognostic marker and
therapeutic target of cancers
1992 Moe and Sprague[35] Osteoblast Mitogen Therapeutic target
2006 Huang etal.[23] Prostate cancer bone metastasis Signaling and growth promoting factor Therapeutic target
2006 Nomura etal.[24] Human renal cell carcinoma Growth stimulator via the 2Mprotein kinase Therapeutic target
ACREBVEGF signaling pathway
2002 Min etal.[18] Myeloma cells Negative growth regulator, induce cell apoptosis Therapeutic strategy
2001 Mori etal.[30] Leukemic cellbearing mice Apoptosisinducing activity via activation of Therapy for leukemia
caspase3 and nuclear factorkappa B
2003 Gordon etal.[31] Human lymphoblastic leukemia Induce apoptosis via increasing reactive oxygen Therapy for leukemia
cell line species
1993 Rock etal.[81] MHC I reconstruction MHC I or like molecules stabilizer Vaccine adjuvant
MHC I: Major histocompatibility complex class I; IL: Interleukin; CREB: cAMP response elementbinding; VEGF: Vascular endothelial growth factor;
2M: Beta 2 microglobulin; IGFI: Insulinlike growth factorI; cAMP: Cyclic adenosine monophosphate.

452 Chinese Medical Journal February 20, 2016 Volume 129 Issue 4
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