Antinuclear Antibodies

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Since ANAs are present in almost all patients with SLE, the ANA test is the most sensitive test for lupus. In a recent study, ANAs were found in 280 out of 291 (96.2%) SLE patients [11]. However, ANAs are not specific for SLE because they occur in a variety of autoimmune, rheumatic, and infectious diseases. Moreover, ANAs are sometimes detected in healthy individuals, especially in the elderly. In any case, the absence of ANAs makes the diagnosis of SLE much less likely, although still possible. Indirect immunofluorescence with tissue or cell culture substrates is the most widely used method for detection of ANAs. Because of their large nucleus and prominent nuclear constituents, human eso-phageal tumor cells (HEp-2) are most commonly used for this purpose. HEp-2 cells have virtually replaced mouse kidney or liver tissue sections because they are much more sensitive for ANAs. The rare anti-Ro/SSA precipitin-positive lupus patient continues to be ANA negative because of the paucity of the Ro/SSA antigen and the loss of its antigenicity after cell fixation.

The ANA test is interpreted both by titer and by pattern. Higher titers loosely correlate with pathologic significance. Since the ANA test is dependent upon immunologic reagents and laboratory conditions, there is substantial inter-laboratory variation [12]. The different antigenic targets bound by the auto-antibody lead to different ANA immunofluorescence patterns, depending on their location within the cell and on the specific changes caused by fixation (Fig. 11.1, see page 253).

Counterimmunoelectrophoresis and immunodiffusion techniques were previously used to detect specific ANAs, but more sensitive techniques have now been developed, for instance, enzyme-linked immunosorbent assays (ELISA) and line immunoassays (LIA) using whole cell nuclei, affinity-purified antigens, recombinant proteins, or synthetic peptides. Immunoblotting [13, 14] and im-munoprecipitation [15, 16] are valuable tools for characterizing many autoanti-bodies that react with nuclear and cytoplasmic antigens. New developments for miniaturization and simultaneous determination of different ANAs and other autoantibodies include novel autoantigen microarrays [17-19] and a laser-based flow technology (Luminex) [20, 21].

Table 11.1 Characterization of autoantigen-autoantibody systems in SLE (modified according to [1, 12, 180, 181]).

Autoantibody Characterization of antigen Biological to function

Prevalence

Disease specificity

Correlation with disease activity

Clinical associations and comments

dsDNA

Histories

Nucleosome

Ul-nRNP

Multiple nuclear antigens (see below)

Double-stranded, native DNA

HI, H2A, H2B, H3, H4, H5, [H2A-H2B]-DNA dimer 140 base pairs of DNA wrapped around 4 pairs of core histones Core proteins B (28), B' (29), D (16), E (13), F and G of Ul, U2, U4, U5, and U6 snRNPs

95-100%

Genetic code 40-80%

Organization of nucleosomes

Organization 50-90% of nuclear DNA

Splicing of 5-70% pre-mRNA

Splicing of pre-mRNA

High

High

High

No One of the revised ACR criteria of SLE; indirect immunofluorescence assay for ANAs is a useful screening test Yes Included in the revised ACR cri teria of SLE, important marker for the diagnosis of SLE; nephritis, CNS involvement Controversial Nephritis? Frequently positive in drug-induced lupus Yes Nephritis, psychosis

Yes Included in the revised ACR cri teria of SLE; more frequent in Asians and Afro-Americans; CNS involvement, milder form of nephritis, lung fibrosis, pericarditis, oral ulcer, thrombopenia, leukopenia, lower prevalence of sicca symptoms; usually found with anti-UlRNP Controversial Raynaud's phenomenon, myositis, arthritis, lower chance for nephritis

Autoantibody

Characterization of antigen

Biological

Prevalence

Disease

Correlation with

Clinical associations

to

function

specificity

disease activity

and comments

RA33

Protein Al (34 kDa) of hnRNP

Splicing of

9-

-40%

No

No

Erosive arthritis

pre-mRNA

Ro/SS-A

52-kDa and 60-kDa ribonucleo-

DNA binding

24-

-60%

No

Controversial

Secondary Sjogren's syndrome,

protein containing small uridine-

protein (52 kDa

subacute-cutaneous lupus, photo

rich nucleic acids (hYl, hY3,

Ro); quality con

sensitivity, neonatal lupus, inter

hY4, hY5)

trol for 5S rRNA

stitial lung disease, lympho

production/

penia, nephritis and anti-DNA

involvement in

in patients without anti-La/SSB

translation of

ribosomal pro

tein rnRNA

(60 kDa Ro)

La/SS-B

Phosphoprotein (48 kDa) asso

Probably tran

6-

-35%

No

No

Secondary Sjogren's syndrome,

ciated with a variety of small

scription termi

neonatal lupus, subacute cuta

RNAs (precursors of cellular 5S

nation factor of

neous lupus, cytopenia, pneumo

RNA and tRNA, 7S RNA, viral

RNA polymer

nitis, leukocytoclastic vasculitis,

RNAs, Ro/SS-A cytoplasmic hY

ase III

C2 and C4 deficiency; lower

RNAs)

prevalence of nephritis and anti-

dsDNA in patients with anti-Ro/

SSA and anti-La/SSB

PCNA

Cyclin (36 kDa)

Auxiliary protein

2-

-7%

High

Not known

Young age of onset, proliferative

of DNA-poly-

nephritis

merase

Table 11.1 (continued)

Autoantibody

Characterization of antigen

Biological

Prevalence

Disease

Correlation with

Clinical associations

to

function

specificity

disease activity

and comments

Ku

Heterodimer consisting of

Repairs dsDNA

10-40%

No

No

Mild disease by a low incidence

70-kDa and 80-86-kDa protein

breaks, V(D)J

of renal and CNS involvement,

subunits, DNA binding compo

recombination

Raynaud's phenomenon, arthri

nent of a 350-kDa catalytic sub-

tis, pulmonary hypertension,

unit with DNA-dependent kinase

esophageal reflux

activity

Ribosomal

Phosphoproteins PO (15 kDa),

Active in elonga

8-42%

High

Yes

Frequencies differ in different

RNP

PI (16 kDa), and P2 (38 kDa)

tion step of pro

ethnic groups; more prevalent

tein synthesis

in juvenile-onset and Asians;

psychosis, hepatitis

Proteasome

Cytoplasmic and nuclear-local-

Involved in the

58%

No

Not known

SLE, Sjogren's syndrome, myo

ized proteinase complex (20S),

ubiquitin-depen-

sitis

arranged in a cylindrical struc

dent selective

ture of 4 stacked rings, each

degradation of

composed of 7 subunits (a-type

short-lived and

subunits form the outer rings,

abnormal pro

jfi-type subunits form the inner

teins; processing

rings carrying the proteolytic

of antigens pre

sites

sented by MHC

class I mole

cules

Clq

Collagen-like region of Clq

Complement

30-50%

No

Yes

Nephritis, hypocomplementemia,

protein that

urticarial vasculitis, predicts

initiates classic

relapses of lupus nephritis,

pathway of com

correlates with anti-dsDNA

plement cascade

Autoantibody

Characterization of antigen

Biological

Prevalence

Disease

Correlation with

Clinical associations

to

function

specificity

disease activity

and comments

Phospholipids,

Negatively charged phospholipids

Role in coagula

20-60%

No

aCL yes

Included in the revised ACR

Lupus

(e.g., cardiolipin, phosphatidyl-

tion

LAC no

criteria of S LE; secondary anti-

anticoagulant

serine), phospholipid-binding

phospholipid syndrome in SLE:

(LAC)

proteins (fil glycoprotein I)

thrombosis recurrent fetal loss, thrombocytopenia, hemolytic anemia, CNS involvement

Red blood

Protein and glycoprotein anti

10-50%

No

No

Hemolytic anemia, often positive

cells

gens on RBC membrane

without anemia, warm antibodies usually detected

Platelets

Major platelet surface glycoproteins (GPIb: 143- and 22-kDa subunits; GPIIb: 132- and 23-kDa subunits; Ilia: 114 kDa; IX: 17-22 kDa)

10-62%

No

Yes

Thrombocytopenia

CD36

Signal transduction, scavenger receptor, and adhesion molecule

nd

nd

No

Thrombopenia, recurrent early fetal loss

Endothelial

Numerous intracellular and

7-86%

No

Yes

Nephritis, CNS involvement,

cells

membrane antigens

pulmonary hypertension, digital vasculitis, Raynaud's phenomenon, serositis, aCL

Fig. 11.1 Immunofluorescence patterns on HEp-2 cells seen in SLE.

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