Autoantibodies and Biomarker Discovery - Proteomic and Metabolomic Approaches to Biomarker Discovery - page 361

ASSOCIATION OF
AUTOANTIBODIES WITH DISEASE
STATES

populations. The five year risk for T1D

approaches 50% in subjects with detectable anti-
bodies against all three antigens. Several clinical
trials targeting these antigens are ongoing. High-
throughput proteomics are being used to iden-
tify novel T1D antigens. However, as the three
known autoantibodies in T1D have excellent
performance as clinical biomarkers, the identifi-

Autoimmune Disorders
The edwere associ-

ated with autoimmune rheumatic diseases. 21,77
Autoantibodies not only indicate the presence
of disease; in some instances, they are pathogenic
causes of in

rst autoantibodies identi

-
cation of new targets may have limited utility
for disease diagnosis or risk prediction. Newly
discovered antigens may still uncover mecha-
nisms of the etiology of T1D for therapeutic
development.

ammation. Even when the autoanti-
bodies are not pathogenic, they may be
biomarkers for antigens that stimulate CD4 þ
cellular immune responses. Traditional IFA
methods to detect antinuclear antibodies,
together with ELISA or radioimmunoassays, are
used for the clinical measurement of these anti-
bodies. Several of the antibodies that have been
identi

Neurologic Disorders
A number of neurologic disorders have
evidence of immune-mediated pathogenesis.
Functional autoantibodies to the acetylcholine
receptor are pathogenic in myasthenia gravis
(MG), as are calcium-channel autoantibodies in
Lambert-Eaton myasthenic syndrome. Paraneo-
plastic neuropathies, primarily associated with
small cell lung cancer and ovarian cancer,
are mediated by cross-reactive autoantibodies
targeting neuronal proteins, such as anti-
Hu/ANNA-1, anti-Ri/ANNA-2, and anti-
Yo/PCA1. 79 However, emerging evidence
suggests that other neurologic disorders, such
as multiple sclerosis, Alzheimer

ed in autoimmune disorders target post-
translational modi cations ( Tables 3 and 4 ).

Anticitrullinated antibodies (ACA) have been
identi c to adult RA,

and distinct antibodies to citrullinated proteins
may be involved in the pathogenesis of the
disease. Clinical testing for ACA using cyclic-
citrullinated-peptides detects RA sera with
a sensitivity of up to 80% to 90% at 98%
speci

ed that are very speci

city.

s dementia,

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Type 1 Diabetes
Type 1 diabetes (T1D) is an autoimmune
disease that is caused by autoimmune destruc-
tion of insulin-secretion islet cells in early child-
hood. Like many autoimmune diseases, both
genetic and environmental factors are thought
to play an important role in disease etiology.
Several autoantibodies, including anti-GAD65
and anti-IA2, have been identi

and Parkinson s disease, may be mediated in

part by B-cell mediated autoimmunity. Multiple
sclerosis (MS) is an autoimmune disease caused
by autoreactive T cells targeting myelin sheaths.
Recent studies have identi

'

ed autoantibodies

that catalyze site-speci c destruction of myelin

basic protein in MS patients 80 and cross-react
with the LMP-1 protein of Epstein-Barr virus. 81
Multiple other autoantibody targets, such as
PGAM1, 82 mtHSP70, 37 and contactin-2, 83 have
been identi

ed in T1D. Using
genomics, the ZnT8 antigen was recently identi-

ed. 78 The presence of these antibodies in sera
indicates the transition from genetic risk to
immunological risk. Both the titer and the
combined frequency of these autoantibodies are
predictive of T1D development

ed in the sera of patients with MS
using proteomic-based approaches. Alzheimer s

dementia is a progressive neurologic disease
marked by accumulation of beta-amyloid and
tau protein in the central nervous system.

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in high-risk