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(Sm) Peptides as Antigens

(Sm) Peptides as Antigens

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TABLE 2

META-ANALYSIS OF ANTI-SM ANTIBODIES

No. (%) positive



Country



Method/antigen used



56/146 (39.2)

30/151 (19.7) a

278/917 (30.3)

32/192 (16.7)

14/187 (7.5)



Tunesia

Dubai

China

United

States



Immunodot/n.p.

n.p./n.p.

Immunoblotting/n.p.

ALBIA

ELISA



50/60 (83.3)



Oman



InnoLIATM ANA Update



216/624 (41.6)



Saudi

Arabia

United

Kingdom

China

Belgium



n.p./n.p.



9/45 (20.0)

469/1584

37/280 (13.6)a,b

79/280 (28.1) a

28/176 (15.9%)b

69/148 (46.6%)



Germany

Germany



n.p./n.p.

InnoLIATM ANA Update SmD

InnoLIATM ANA Update SmB

ELISA, SmD3 peptide with sDMA

ELISA IMTEC-SmD1-Antibodies,

ITC60029/SmD1 peptide

ELISA/SmD1 peptide (without sDMA)



117/167 (70.0)



Germany



21/113 (18.6)



Israel



7/123 (5.7)b

10/123 (8.1)

22/123 (17.9)

40/111 (36.0)



Belgium



Germany



1584/5550 (28.5%)



All



AtheNA Multi-LyteÒ Anti-Nuclear

Antibodies (ANA)

ELISA, Phadia/native SmD1

CIA

LIA recomLine ANA/ENA (Mikrogen)

ELISA IMTEC-SmD1-Antibodies,

ITC60029/SmD1 peptide

Diverse



72/579 (12.4%)



All



Diverse



a

b



Comment



Association with Malar rash, pericarditis, leukopenia

Association with SLEDAI (stronger with ELISA than

with BioPLEX)

ELISA data from different kit manufacturer

No information provided with Sm antigen was

interpreted; high prevalence



Reference

[87]

[86]

[91]

[63]



[88]

[89]



P ¼ 0.57 with SLEDAI



[83]



Trend to early disease

Unclear how many SLE had anti-Sm antibodies



[90]

[59]

[69]

[72]



Correlation with dsDNA antibodies and

disease activity



[29]

[93]

[57]



[70]

Meta-analysis of all studies and all methods

within one study

Anti-SmD onlyb



Information in the method was missing. Number of positive patients were calculated or estimated (in case discrepancies were observed).

Included into the meta-analysis.



SM PEPTIDES IN DIFFERENTIATION OF AUTOIMMUNE DISEASES



121



advanced research in the fields of chemistry, biochemistry, molecular

biology, and medicine.

Modification of peptides is of high interest for autoimmune research,

diagnostics, and therapeutics. The most widespread modifications are biotinylation, fluorescent labels, methylation, phosphorylation, disulfidebridged cyclic peptides, MAP-peptides, branched peptides, and peptides

containing nonnatural amino acids. Arginine residues in the C-terminal

part of the Sm polypeptides become methylated by the methylosome, a

complex of type II methyltransferases, which significantly enhances the

affinity of the Sm polypeptides to the survival motor neuron (SMN) complex, a machine designed to bind Sm proteins (reviewed in Refs. [2,19]).

Depending on the amino acid sequence, the length, and the biochemical

properties of the peptide of interest, one of the following coupling strategies

can be used to link the peptide to the solid phase of the respective immunoassay (e.g., microtiter plate). Peptides with a length of more than 10 amino

acids and an isoelectric point of more than 8 can directly be coated onto

microtiter plates [48]. Alternatively, peptides can be covalently bound to

paramagnetic particles which are commonly used with chemiluminescence

analyzers. Depending on the structure of the peptide, there is a risk of

blocking the epitope when direct coating is used. To increase the absorption

properties of synthetic peptides, the peptide must be converted to high

molecular weight products. This can be achieved using two strategies. The

first possibility is to synthesize the peptide on a special resin, the so-called

MAP resin (MAP — multiple antigen peptide). In this approach, four to

eight copies of the peptide are synthesized on a polylysine core. After cleavage from the synthesis resin, the resulting MAP construct reaches a molecular weight of about 13–17 kDa, which is sufficient for direct coating onto

microtiter plates. Alternatively, the peptide of interest can be covalently

coupled to the so-called carrier proteins such as human serum albumin

(HSA) or bovine serum albumin (BSA), keyhole limpet hemocyanin (KLH)

or ovalbumin (OVA), which leads to a surface exposure of the peptide and to

a higher accessibility of the epitope. Sophisticated surface modifications of

mircotiter plates, microbeads, or microchips allow for the covalent and direct

linking of peptides to the respective surface. Similarly, avidin coated surfaces

can be used to immobilize biotinylated peptides with high affinity.

Once a synthetic peptide is recognized by a considerable number of sera

within a defined cohort of patients with a certain autoimmune disease, it

represents an ideal antigenic target for immunoassays because it can be easily

produced in high quality and quantity. Furthermore, lower lot to lot variations will be observed since the production is not dependent on the biological

variation of native sources of antigens. On the other hand, there are pitfalls

to the use of synthetic peptides. False positive results may seldom occur



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MICHAEL MAHLER



because the peptides share amino acid sequences with foreign or self antigens,

or because chemical conjugation alters the antigenicity of the peptide.

Nevertheless, today’s sophisticated epitope mapping methods [9] will likely

lead to the identification of additional peptides, which can be used as specific

targets in diagnostic and therapeutic approaches to patient management.

This may lead to a new scientific research area with high impact for the

development of diagnostic and therapeutic products, in the area of peptide

engineering.



12. Summary and Conclusion

Anti-SmD antibodies represent a specific marker for SLE. Although antiSm antibodies target various antigens, only highly purified SmD or synthetic

SmD1 or SmD3 peptides are specific antigens for the diagnosis of SLE. Based

on our meta-analysis we conclude that anti-Sm antibodies are found in 28.5%

and anti-SmD antibodies in 12.4% of SLE patients.



13. Take Home Messages

 Anti-SmD antibodies have high disease specificity for SLE but a low

sensitivity (10–20%).

 SmBB0 contains a cross-reactive epitope which is also present in U1RNPs.

 SmD1/D3 peptides containing symmetrical dimethyl arginine or highly

purified SmD represent the preferred antigens for anti-Sm antibody

detection.

 The Sm antigen is the target of IgM, IgG, and IgE isotypes.

 Molecular mimicry might play an important role in the genesis of antiSm antibodies.



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ADVANCES IN CLINICAL CHEMISTRY, VOL. 54



AROMATASE ACTIVITY AND BONE LOSS

Luigi Gennari,1 Daniela Merlotti, and Ranuccio Nuti

Department of Internal Medicine, Endocrine-Metabolic

Sciences and Biochemistry, University of Siena, Siena, Italy



1.

2.

3.

4.

5.



6.

7.

8.



9.



Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Aromatase and Sources of Estrogen Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

The Aromatase Gene and Its Tissue-Specific Regulation. . . . . . . . . . . . . . . . . . . . . . . . .

Aromatase Deficiency and the Bone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5.1. Aromatase Deficiency Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5.2. Animal Models of Aromatase Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5.3. Inhibition of Aromatase Activity: Clinical Studies in Men. . . . . . . . . . . . . . . . . .

5.4. Inhibition of Aromatase Activity: Use of AIs in Women . . . . . . . . . . . . . . . . . . .

Skeletal Consequences of Aromatase Excess . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Threshold Estradiol Hypothesis for Skeletal Sufficiency . . . . . . . . . . . . . . . . . . . . . . . . .

Variability in the Level of Aromatase Activity: Effects on Bone Metabolism . . . . .

8.1. Inherited Variation in Aromatase Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8.2. Acquired Variation in Aromatase Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .



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1. Abstract

Aromatase is a specific component of the cytochrome P450 enzyme system that

is responsible for the transformation of C19 androgen precursors into C18

estrogenic compounds. This enzyme is encoded by the CYP19A1 gene located

at chromosome 15q21.2, that is expressed in ovary and testis not only but also in

many extraglandular sites such as the placenta, brain, adipose tissue, and bone.

The regulation of the level and activity of aromatase determines the levels of

estrogens that have endocrine, paracrine, and autocrine effects on target issues

including bone. Importantly, extraglandular aromatization of circulating

1



Corresponding author: Luigi Gennari, e-mail: gennari@unisi.it

129



0065-2423/11 $35.00

DOI: 10.1016/B978-0-12-387025-4.00006-6



Copyright 2011, Elsevier Inc.

All rights reserved.



130



GENNARI ET AL.



androgen precursors is the major source of estrogen not only in men (since only

15% of circulating estradiol is released directly by the testis) but also in women

after the menopause. Several lines of clinical and experimental evidence now

clearly indicate that aromatase activity and estrogen production are necessary

for longitudinal bone growth, attainment of peak bone mass, the pubertal

growth spurt, epiphyseal closure, and normal bone remodeling in young individuals. Moreover, with aging, individual differences in aromatase activity and

thus in estrogen levels may significantly affect bone loss and fracture risk in both

genders.



2. Introduction

Sex steroid hormones are important for the acquisition and maintenance

of bone mass in both sexes [1,2]. Alterations in their levels can become

relevant in the pathogenesis of osteoporosis either because their deficiency

leads to suboptimal acquisition of peak bone mass or because deficits in

adulthood can directly lead to bone loss. While estrogens have been shown to

be critically important in these respects for the female skeleton (as estrogen

deficiency after menopause leads to an imbalance between bone resorption

by osteoclasts and bone formation by osteoblasts), the role for estrogen in

male skeletal health has only recently become appreciated [3–6]. This is due,

in part, to attributions of gender-specific effects: estrogens for women;

androgens for men. The assumption is rational especially since circulating

androgens predominate in men and estrogens predominate in women.

In addition, alterations in circulating androgen in the growing male skeleton

or in the context of the aging male skeleton have been associated with low

bone mass and impaired bone strength [7]. However, while androgens are

undoubtedly playing a role in male skeletal health, their primacy has been

increasingly questioned as direct and indirect evidence has emerged suggesting that estrogens also play a major role in male skeletal health [3–7]. These

new observations underscore the normal biosynthetic pathway by which

estrogens are made. In fact, estrogens in men are mainly derived from androgens via the activity of aromatase, a cytochrome P450 product of the

CYP19A1 gene [8–10]. The obligate precursors are the androgenic steroids.

The human P450 aromatase enzyme is found in many tissues such as placenta,

ovary, testis, brain, adipocyte, and also in bone. Moreover, peripheral aromatization of adrenal androgen precursors also represents a major source of

estrogen in women after menopause for many target tissues including bone.

This review summarizes the evidence that aromatase activity plays an

important role in the skeleton in females as well as in males by its actions

to convert androgens to estrogens.



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