www.elsevier.com/locate/autrev

Autoimmunity Reviews 4

Complex genetics of Wegener granulomatosis

Peter Jagielloa,*, Wolfgang L. Grossb, Jfrg T. Epplena

aDepartment of Human Genetics, Ruhr-University Bochum, Universitaetsstrasse 150, 44801 Bochum, GermanybRheumatology, Medizinische Universitatsklinik Lubeck and Rheumaklinik Bad Bramstedt, Germany

Received 1 June 2004; accepted 23 June 2004

Available online 26 July 2004

Abstract

Wegener granulomatosis (WG) belongs to a heterogeneous group of systemic anti-neutrophil cytoplasmatic antibody

(ANCA) associated vasculitides (AASV). WG is characterized by necrotizing granulomatous inflammation of the upper and

lower respiratory tract, glomerulonephritis and vasculitis. As a multifactorial model disease, WG is hallmarked by the

presence of specific ANCA-subtypes directed against a defined antigen. WG is more predominant among Caucasians and

the genetic predisposition appears quite complex. Here, we provide a brief overview concerning genetic factors in the

pathogenesis of WG and discuss intricacies of molecular genetic approaches.

D 2004 Elsevier B.V. All rights reserved.

Keywords: Wegener granulomatosis; Multifactorial disease; Predisposing genetic factor

Contents

1. Conclusions and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

Systemic vasculitides (SV) such as giant cell

arteritis, Takayasu arteritis, Kawasaki disease and

Wegener granulomatosis (WG) are characterized by a

primary process of inflammation and damage of blood

1568-9972/$ - see front matter D 2004 Elsevier B.V. All rights reserved.

doi:10.1016/j.autrev.2004.06.003

* Corresponding author. Tel.: +49 234 3223831; fax: +49 234

3214196.

E-mail address: peter.jagiello@rub.de (P. Jagiello).

vessel walls [1]. Differentiation of defined entities in

this enigmatic group of SV is often problematic, based

on the variety of clinical symptoms and the similar-

ities in histology. So far, SV are differentiated by size

of affected vessels, i.e. large vessels (e.g. Takayasu

arteritis), intermediate vessels (e.g. Kawasaki disease)

and small vessels (e.g. WG, microscopic polyangiitis

[MPA] or Churg–Strauss syndrome [CSS]). A feature

(2005) 42–47

P. Jagiello et al. / Autoimmunity Reviews 4 (2005) 42–47 43

of the last-mentioned group concerns the presence of

anti-neutrophil cytoplasmatic antibody (ANCA) that

act as diagnostic markers positively correlating with

disease activity [2]. Whereas ANCA against myelo-

peroxidase (MPO-ANCA) occur in MPA and CSS,

proteinase 3 (PRTN3-)ANCA are observed in patients

suffering from WG [2].

Several findings suggest genetic predisposition

factors for WG [3]. Therefore, ANCA target genes

were already extensively investigated. The membrane

expression of the main ANCA target antigen PRTN3

(previously designated as PR-3) is genetically deter-

mined [4]. In addition, association of a promoter

polymorphism in the PRTN3 gene with WG has been

demonstrated affecting a putative SP1-transcription

factor-binding site [5]. This polymorphism leads

potentially to increased PRTN3 expression. PRTN3

belongs to the serine proteinase family, which is

inhibited by the serin protease inhibitors (serpins),

their genes clustering (in addition to further loci) at

chromosome 14q32.1. Interestingly, linkage disequi-

librium in this gene cluster points to associated

haplotypes with WG [6]. Moreover, association

studies concerning the PRTN3 inhibitor alpha1-

antitrypsin (a1-AT) gene showed that the frequency

the a1-AT deficiency allele PI*Z is increased in WG

patients. Yet, the carriers of this allele did not suffer

from any vasculitis symptoms in a larger population

of PI*Z+ individuals [7].

Whenever ANCA are demonstrable, infectious

aetiologies may be discussed and, therefore, a relation

between (polymorphonuclear neutrophil [PMN]-medi-

ated) host defence and ANCA induction appears

conceivable. For example, PMN-derived antibiotic

proteins represent a source of innate immune defence

playing a role in recognition and neutralization of the

proinflammatory surface components (e.g. endotoxins)

of bacteria [8]. Interestingly, most of these molecules

are target antigens for ANCA [9]. Yet, in 6% of ANCA

associated vasculitides (AASV), bactericidal/perme-

ability-increasing protein (BPI)-ANCA is detected.

Therefore, in a further association study, the function-

ally relevant Glu216Lys polymorphism of theBPI gene

has been genotyped (Jagiello et al., unpublished data).

Comparison of allele frequencies and genotypes did not

reveal differences between WG patients and healthy

controls. In addition, alleles of an ad hoc designed in-

tragenic microsatellite marker were not linked to WG.

Binding of ANCA to antigens on the surface of

PMN results in cellular activation as mediated by Fcg

receptors (FcgR) [10]. Most analyses of these highly

polymorphic genes did not show significant differences

in genotype distributions or allele frequencies between

patients and controls. Yet, a trend for increased

homozygosity of the FcgRIIIb-NA1 allele was evident

which may have implications for disease susceptibility

being significant in MPO-ANCA+ patients [11]. In

addition, WG patients were more prone to disease

relapse if they were homozygous for, both, the R131

isoform of FcgRIIa and the F158 isoform of

FcggRIIIa. This fact might be related to chronic nasal

carriage of Staphylococcus aureus and the inability of

the immune system to eliminate this bacterium,

respectively [12]. Furthermore, adhesiveness of leuko-

cytes to the endothelium is an important pathophysio-

logical element of WG. Adhesion is augmented by

expression of molecules like CD11, CD18, ICAM-1

and E-selectin. Whereas studies did not reveal specific

associations in the aforementioned genes as risk factors

for WG, linkage was evidenced between given CD18

alleles and MPO-ANCA vasculitides [13].

Many autoimmune disorders are characterized by

predominance of T helper 1 (Th1) cells, the cytokine

pattern of which has also been observed in granulo-

mata of WG patients [14]. As the cytotoxic T cell

antigen 4 (CTLA4) has a role in inducing a Th1

response also by suppressing Th2 cytokines, poly-

morphisms in the CTLA4 gene were investigated. In a

small WG cohort, an association of a simple AT repeat

polymorphism in the 3V-untranslated region was

identified [15]. In T cells from patients with myas-

thenia gravis longer AT dinucleotide blocks cause

reduced expression of CTLA-4 due to decreased

mRNA stability [16]. A second single nucleotide

polymorphism (SNP) in the promoter region revealed

association with WG [17], but relevance for WG

pathogenesis has still to be demonstrated, as this SNP

is not comprised in any known consensus sequence,

e.g. for transcription factor binding sites or other

regulatory elements. Another SNP results in amino

acid exchange (Y to A, position 49) without any

association. Interestingly, linkage disequilibrium was

demonstrated between the Y residue and the shortest

allele of the AT microsatellite in controls but not in

patients [17]. The functional significance of the

genotypes for protection against WG remains elusive.

P. Jagiello et al. / Autoimmunity Reviews 4 (2005) 42–4744

Studies on gene polymorphism in cytokines,

chemokines and their receptors have also been carried

out. In this context, SNPs in the tumor necrosis factor

(TNF) genes were investigated whereby a TNFa

promotor polymorphism at position �308 and an

intronic SNP in the TNFh gene did not reveal

statistically significant differences between patients

and controls [18]. Yet concerning the clinical course

of the disease, WG patients with a defined TNF 1/1

phenotype were found to have a higher mean disease

extension index than TNF 1/2 individuals [18]. In part

these results were confirmed in a later study that, on

the other hand, excluded certain interleukin 2 (IL2)

and IL5 receptor (IL5R)a alleles as predisposing

genetic factors [19]. Furthermore, polymorphisms in

the genes for IL1h and IL1Ra were examined

concerning the clinical manifestation and outcome

of AASV [20]. A distinct combination of these

polymorphisms leads to a pro-inflammatory genotype

increased in PRTN3-ANCA+ patients with end-stage-

renal disease [20]. In a Swedish WG population

variations in the IL4 and IL10 genes were investigated

[21]. Both IL4 and IL10 belong to Th2 cytokine

pattern and reduced levels of these anti-inflammatory

cytokines might be related to WG manifestation.

While IL4 variations did not reveal an association

with WG, a so-called microsatellite polymorphism

located in the promotor region of IL10 showed a

significantly higher percentage of patients heterozy-

gous for two specific alleles [21]. In addition, in

another study on Caucasians, a significant shift

toward the homozygous AA genotype of an IL10

polymorphism was observed in WG patients. Fur-

thermore, the latter study excluded the polymorphism

in codon 25 of the transforming growth factor b1

(TGFb1) gene as a genetic risk factor for WG [22].

Human leukocyte antigen (HLA) genes are exceed-

ingly polymorphic and numerous studies have implied

factors in the major histocompatibility complex (MHC)

for susceptibility to autoimmune diseases (see e.g. Ref.

[23,24]). HLA genes encode cell surface molecules

initiating acquired immune responses to invading

pathogens (potentially also S. aureus for WG). Poly-

morphic HLA genes were extensively studied in order

to determine possible associations with WG. Different

alleles were increased in frequency in WG patients like

HLA-B8, -B50, -DR9, -DR1, -DR2, -DQw7 and the

haplotype HLA-DR4DQ7 [24–29], respectively,

whereas a decrease of HLA-DR3 alleles and HLA-

DR13DR6 heterozygotes among WG or SV patients

has also been observed [29,30]. Most of these studies

revealed no consistent or, better, exclusively spurious

associations, largely depending on the number of

patients investigated. In a recent systematic association

screen with 202 microsatellites certain alleles within

chromosome region 6p21.3 were significantly associ-

ated with WG [31]. HLA-DPB1 genotyping of this

comparatively large cohort of 150 patients revealed an

increased frequency of the DPB1*0401 allele. In

contrast, the frequency of the *0301 allele was

significantly decreased. These results were confirmed

in an independent WG patient cohort [31]. Although

these genes present veritable candidates, WG predis-

position based on adjacent factors is difficult to be

differentiated due to extensive linkage disequilibrium

(LD). Genotyping of SNPs spanning 200 kb of the

abovementioned region differed significantly between

patients and controls, as well, clustering at the HLA-

DPB1 and retinoid X receptor b (RXRB) genes. Among

other functions RXRB protein forms heterodimers with

vitamin D receptors (VDR) and dimerization with

VDR plays an important role in forming the soluble

vitamin D3 metabolite, 1,25-dihydroxyvitamin D3

[32]. This metabolite harbours anti-inflammatory

effects due to inhibition of cytokine transcription

required for Th1 differentiation [33,34]. In addition,

haplotypes spanning the HLA-DPB1 and RXRB genes

reinforced the association ofDPB1 and RXRB markers,

thus presenting a predisposing and a protective

haplotype [31]. In conclusion, this genomic region

appears as the major risk factor for WG.

Furthermore, two additional loci (Casp14 and re-

ceptor (TNFRSF)-interacting serine-threonine kinase

1 [Ripk1]) represent good candidates for WG predis-

position. Polymorphisms in these genes may cause

subtle shifts in the balance of apoptosis [31]. Apoptosis

appears critically involved in (auto)immune reactions

in terms of deither too little or too muchT [35,36].

Firstly, autoreactive immune cells are eliminated and

inactivated by apoptosis. This process might be dis-

rupted by decreased apoptosis leading to loss of self-

tolerance. On the other hand, augmented apoptosis in

cells surrounding WG foci might enhance pro-inflam-

matory responses and finally the self-sustaining in-

flammatory process (references in Ref. [31]). Whereas

the expression of Casp14 is keratinocyte specific [37]

P. Jagiello et al. / Autoimmunity Reviews 4 (2005) 42–47 45

and a relationship to WG appears doubtful, Ripk1 is

directly involved in apoptosis through interacting with

TNFRSF1A-associated via death domain (TRADD).

This interaction recruits RIPK1 to TNFR1, which

triggers pathways leading to apoptosis and activation

the nuclear factor of n light chain gene enhancer in B

cells [38]. Yet, the relevance of these findings remain to

be ascertained on the functional level.

1. Conclusions and future directions

The pathophysiology of complex diseases has not

yet been deciphered in detail and, like in WG,

candidates for genetic predisposition are truly abun-

dant. In WG such candidates represent genes of diverse

dfunctional systemsT comprising molecules involved in

Fig. 1. Phenotypes of WG patients as determined theoretically by gene–gen

variations are related to the manifestation of the WG phenotypes. (1) Ma

symptoms of WG (e.g. HLA-DPB1). Several genetic variations can act—w

(2) Variations of multiple loci (specific genotypes) apparently have combin

alone might not differ significantly when compared between patients an

sequence variations is thought to be due to epistasis, so-called gene–ge

symptoms. The equilibrium of the genes’ concerted actions is disturb

physiological homeostases. Consequently imbalanced expression of, e.g

resulting potentially in WG phenotypes, finally. (C) WG phenotypes (seve

rather they are distributed continuously as influenced by delicate combinati

effects of several genes plus environmental factors.

e.g. T cell or PMN activation, Th1 or Th2 response,

host defence and apoptosis. In general, each individual

observed genetic variation is neither necessary nor

sufficient to explain the pathogenetic mechanisms for

WG manifestation and development. Apparently,

environmental plus a number of genetic predisposition

factors influence the manifestation of WG (Fig. 1).

Additional predisposing genes will be investigated

by diverse genotyping methods potentially revealing

further genetic variations associated with WG. In this

scenario, it appears timely to focus on diligent

evaluation of combinations and/or interactions

between polymorphisms, both of statistically signifi-

cant major effects but also of genetic factors harbouring

no or minimal main effects by themselves. Existing

variations have to be confirmed in distinct WG

populations, which must be homogenous in clinical

e and by gene–environment interactions. (A) Several genetic factors/

jor independent effects may predict the WG phenotype or distinct

henever N1 is involved—in either additive or non-additive manner.

ed effects on the WG phenotype. Respective alleles from one locus

d controls (minimal non-additive effects). The influences of such

ne and/or biomolecular interactions, respectively, enhancing WG

ed. (B) Environmental factors (e.g. bacterial infections) disturb

., transcription factors leads to altered biomolecular interactions

rity of symptoms, outcome, etc.) do not appear in a discrete manner,

ons of direct genetic, direct environmental and intermingled indirect

P. Jagiello et al. / Autoimmunity Reviews 4 (2005) 42–4746

course, serological data and ANCA status as well as

perhaps also in therapeutic responses. On the other

hand, physiological polymorphisms in genes of distinct

functional systems or pathways have to be investigated

in the pathogenesis of WG using appropriate statistics.

Because of the low prevalence ofWG, such approaches

are obviously prone to be worked out in larger

consortia-in addition to further necessary innovations

in the molecular genetic and statistical procedures.

Take-home messages

! WG is a complex disease of unknown aetiology

involving multiple genetic factors.

! Since the nominal antigen in WG is known, the

pathophysiology can be unravelled systematically

! The strongest association in WG concerns a

protective and a predisposing haplotype, respec

tively, on chromosome 6 comprising distinct HLA

DPB1 alleles.

! Autoimmune phenomena of WG may be influ

enced by variations in apoptosis-related genes

inter alia.

! Specific combinations of dcommon allelesT have tobe evaluated in order to understand the genetic

components in the pathogenesis of multifactoria

diseases.

.

-

-

-

,

l

References

[1] Gross WL. Immunopathogenesis of vasculitis. In: Klippel JH,

Dieppe PA, editors. Rheumatology, 2nd ed. London7 Mosby,

1998. p. 7.19.1–19.8.

[2] Falk RJ, Nachman PH, Hogan SL, Jennette JC. ANCA

glomerulonephritis and vasculitis: a Chapel Hill perspective.

Semin Nephrol 2000;20:233–43.

[3] Mahr A, Guillevin L, Poissonnet M, Ayme S. Prevalences of

polyarteritis nodosa, microscopic polyangiitis, Wegener’s

granulomatosis, and Churg–Strauss syndrome in a French

urban multiethnic population in 2000: a capture–recapture

estimate. Arthritis Rheum 2004;51:92–9.

[4] Schreiber A, Busjahn A, Luft FC, Kettritz R. Membrane

expression of proteinase 3 is genetically determined. J Am Soc

Nephrol 2003;14:68–75.

[5] Gencik M, Meller S, Borgmann S, Fricke H. Proteinase 3 gene

polymorphisms and Wegener’s granulomatosis. Kidney Int

2000;58:2473–7.

[6] Borgmann S, Endisch G, Urban S, Sitter T, Fricke H. A

linkage disequilibrium between genes at the serine protease

inhibitor gene cluster on chromosome 14q32.1 is associated

with Wegener’s granulomatosis. Clin Immunol 2001;98:

244–8.

[7] Audrain MA, Sesboue R, Baranger TA, Elliott J, Testa A,

Martin JP, et al. Analysis of anti-neutrophil cytoplasmic

antibodies (ANCA): frequency and specificity in a sample of

191 homozygous (PiZZ) alpha1-antitrypsin-deficient subjects.

Nephrol Dial Transplant 2001;16:39–44.

[8] Levy O. Antibiotic proteins of polymorphonuclear leukocytes.

Eur J Haematol 1996;56:263–77.

[9] Hoffman GS, Specks U. Antineutrophil cytoplasmatic anti-

bodies. Bull Rheum Dis 1998;47:5–8.

[10] Kocher M, Siegel ME, Edberg JC, Kimberly RP. Cross-linking

of Fc gamma receptor IIa and Fc gamma receptor IIIb induces

different proadhesive phenotypes on human neutrophils. J

Immunol 1997;159:3940–8.

[11] Tse WY, Abadeh S, Jefferis R, Savage CO, Adu D. Neutrophil

FcgammaRIIIb allelic polymorphism in anti-neutrophil cyto-

plasmic antibody (ANCA)-positive systemic vasculitis. Clin

Exp Immunol 2000;119:574–7.

[12] Dijstelbloem HM, Scheepers RH, Oost WW, Stegeman CA,

van der Pol WL, Sluiter WJ, et al. Fcgamma receptor

polymorphisms in Wegener’s granulomatosis: risk factors for

disease relapse. Arthritis Rheum 1999;42:1823–7.

[13] Gencik M, Meller S, Borgmann S, Sitter T, Menezes Saecker

H, Fricke H, et al. The association of CD18 alleles with anti-

myeloperoxidase subtypes of ANCA-associated systemic

vasculitides. Clin Immunol 2000;94:9–12.

[14] Steiner K, Moosig F, Csernok E, Selleng K, Gross WL,

Fleischer B, et al. Increased expression of CTLA-4 (CD152)

by T and B lymphocytes in Wegener’s granulomatosis. Clin

Exp Immunol 2001;126:143–50.

[15] Huang D, Giscombe R, Zhou Y, Lefvert AK. Polymorphisms

in CTLA-4 but not tumor necrosis factor-alpha or interleukin

1beta genes are associated with Wegener’s granulomatosis. J

Rheumatol 2000;27:397–401.

[16] Wang XB, Kakoulidou M, Giscombe R, Qiu Q, Huang D,

Pirskanen R, et al. Abnormal expression of CTLA-4 by T cells

from patients with myasthenia gravis: effect of an AT-rich gene

sequence. J Neuroimmunol 2002;130:224–32.

[17] Giscombe R, Wang X, Huang D, Lefvert AK. Coding sequence

1 and promoter single nucleotide polymorphisms in the CTLA-

4 gene in Wegener’s granulomatosis. J Rheumatol 2002;29:

950–3.

[18] Mascher B, Schmitt W, Csernok E, Tatsis E, Reil A, Gross WL,

et al. Polymorphisms in the tumor necrosis factor genes in

Wegener’s granulomatosis. Exp Clin Immunogenet 1997;14:

226–33.

[19] Gencik M, Borgmann S, Zahn R, Albert E, Sitter T, Epplen JT,

et al. Immunogenetic risk factors for anti-neutrophil cytoplas-

mic antibody (ANCA)-associated systemic vasculitis. Clin

Exp Immunol 1999;117:412–7.

[20] Borgmann S, Endisch G, Hacker UT, Song BS, Fricke H.

Proinflammatory genotype of interleukin-1 and interleukin-1

receptor antagonist is associated with ESRD in proteinase

P. Jagiello et al. / Autoimmunity Reviews 4 (2005) 42–47 47

3-ANCA vasculitis patients. Am J Kidney Dis 2003;41:

933–42.

[21] Zhou Y, Giscombe R, Huang D, Lefvert AK. Novel genetic

association of Wegener’s granulomatosis with the interleukin

10 gene. J Rheumatol 2002;29:317–20.

[22] Bartfai Z, Gaede KI, Russell KA, Murakozy G, Muller-

Quernheim J, Specks U. Different gender-associated genotype

risks of Wegener’s granulomatosis and microscopic polyan-

giitis. Clin Immunol 2003;109:330–7.

[23] Wucherpfennig KW. Insights into autoimmunity gained from

structural analysis of MHC-peptide complexes. Curr Opin

Immunol 2001;13:650–6.

[24] Griffith ME, Pusey CD. HLA genes in ANCA-associated

vasculitides. Exp Clin Immunogenet 1997;14:196–205.

[25] Katz P, Alling DW, Haynes BF, Fauci AS. Association of

Wegener’s granulomatosis with HLA-B8. Clin Immunol

Immunopathol 1979;14:268–70.

[26] Cotch MF, Fauci AS, Hoffman GS. HLA typing in patients

with Wegener granulomatosis. Ann Intern Med 1995;122:635.

[27] Boki KA, Kurki P, Holthofer H, Tzioufas AG, Drosos AA,

Moutsopoulos HM. Prevalence of antikeratin antibodies in

Greek patients with rheumatoid arthritis. A clinical, serologic,

and immunogenetic study. J Rheumatol 1995;22:2046–8.

[28] Elkon KB, Sutherland DC, Rees AJ, Hughes GR, Batchelor JR.

HLA antigen frequencies in systemic vasculitis: increase in

HLA-DR2 in Wegener’s granulomatosis. Arthritis Rheum

1983;26:102–5.

[29] Spencer SJ, Burns A, Gaskin G, Pusey CD, Rees AJ. HLA

class II specificities in vasculitis with antibodies to neutrophil

cytoplasmic antigens. Kidney Int 1992;41:1059–1063.

The World of Autoimmunity; Literature Synopsis

Thyroid autoimmunity and the risk of miscarriage

534 pregnant women have been screened for thyroid pero

free thyroxine (fT4) levels. Sieiro Netto et al. (Am J Rep

loss or live birth rate in these patients. In this cohort, 29

significantly higher in this group compared with TPO-Ab

Elevated TSH levels were found in 13.8% (4 of 29) of the

(12 of 505) of the TPO-Ab-negative women. The overall

was significantly higher among women older than 35

presenting high levels of TSH (12.5%). The authors con

associated with is a higher risk of miscarriage.

[30] Hagen EC, Stegeman CA, D’Amaro J, Schreuder GM, Lems

SP, Tervaert JW, et al. Decreased frequency of HLA-

DR13DR6 in Wegener’s granulomatosis. Kidney Int 1995;48:

801–5.

[31] Jagiello P, Gencik M, Arning L, Wieczorek S, Kunstmann E,

Csernok E, et al. New genomic region for Wegener’s gran-

ulomatosis as revealed by an extended association screen with

202 apoptosis-related genes. Hum Genet 2004;114:468–77.

[32] Prufer K, Barsony J. Retinoid X receptor dominates the

nuclear import and export of the unliganded vitamin D

receptor. Mol Endocrinol 2002;16:1738–51.

[33] Topilski I, Flaishon L, Naveh Y, Harmelin A, Levo Y, Shachar

I. The anti-inflammatory effects of 1,25-dihydroxyvitamin D3

on Th2 cells in vivo are due in part to the control of integrin-

mediated T lymphocyte homing. Eur J Immunol 2004;34:

1068–76.

[34] Adorini L. Immunomodulatory effects of vitamin D receptor

ligands in autoimmune diseases. Int Immunopharmacol 2002;

2:1017–28.

[35] Todaro M, Zeuner A, Stassi G. Role of apoptosis in

autoimmunity. J Clin Immunol 2004;24:1–11.

[36] Gordon C, Salmon M. Update on systemic lupus erythema-

tosus: autoantibodies and apoptosis. Clin Med 2001;1:10–4.

[37] Rendl M, Ban J, Mrass P, Mayer C, Lengauer B, Eckhart L, et

al. Caspase-14 expression by epidermal keratinocytes is

regulated by retinoids in a differentiation-associated manner.

J Invest Dermatol 2002;119:1150–5.

[38] Hsu H, Huang J, Shu HB, Baichwal V, Goeddel DV. TNF-

dependent recruitment of the protein kinase RIP to the TNF

receptor-1 signaling complex. Immunity 1996;4:387–96.

xidase antibodies (TPO-Abs), thyrotropin (TSH) and

rod Immunol 2004;52:312) evaluated the pregnancy

(5.4%) were TPO-Ab positive, the TSH levels were

negative women (median; 1.9 versus 1.1; P = 0.001).

TPO-Ab-positive women compared with only 2.4%

risk of miscarriage was 2.4% (13 of 534). This risk

years (7.7%), TPO-Ab positive (10.3%) and those

cluded that thyroid autoimmunity is independently