Genetic underpinnings of autoimmunity — lessons from studiesin arthritis, diabetes, lupus and multiple sclerosisKirthi Raman� and Chandra Mohany

Autoimmunity has been studied for more than four decades, but

its genetic origins have remained a mystery. The recent past has

witnessed an exponential growth in our understanding of

autoimmunity resulting from both forward and reverse genetic

approaches. More than 40 genes have been shown to precipitate

systemic autoimmunity when genetically manipulated. In

addition, reverse genetic studies in various autoimmune

diseases have successfully guided researchers to specific

locations on the genome that are associated with disease

susceptibility. Buried within these genomic intervals lies a further

treasure chest of autoimmunity genes. Efforts to unmask these

culprit genes have yielded the very first clues about how an

elaborate cast of players may be at work to orchestrate

autoimmunity.

AddressesSimmons Arthritis Research Center, Department of Internal Medicine/

Rheumatology, UT Southwestern Medical Center, Mail Code 8884,

Y8.204 5323, Harry Hines Boulevard, Dallas, TX 75390-8884, USA

Correspondence: Chandra Mohan, MD, PhD�e-mail: kirthi.raman@utsouthwestern.uduye-mail: chandra.mohan@utsouthwestern.edu

Current Opinion in Immunology 2003, 15:651–659

This review comes from a themed issue on

Autoimmunity

Edited by Nora Sarvetnick and Pamela S Ohashi

0952-7915/$ – see front matter

� 2003 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.coi.2003.09.007

AbbreviationsCIA collagen-induced arthritis

EAE experimental allergic encephalomyelitis

IDDM insulin-dependent diabetes mellitus

MS multiple sclerosis

PGIA proteoglycan-induced arthritis

QTL quantitative trait loci

RA rheumatoid arthritis

SLE systemic lupus erythematosus

TMEVD Thieler’s murine encephalomyelitis virus induced

demyelination

IntroductionEarly studies indicated that autoimmunity was not mono-

genic in origin, but little did anyone imagine it was going

to be so plurally polygenic. The list of genetic intervals

and loci associated with susceptibility to autoimmunity

arising from genetic studies in patient populations and

rodents has grown almost exponentially since the end

of the twentieth century. The goal of this review is to

provide a snapshot of the documented autoimmunity

susceptibility loci and genes as of 2003, as well as to

highlight salient research contributions over the past year.

Both forward and reverse genetic studies have contributed

to the rich assembly of genetic loci presented in this

review. Forward genetic approaches essentially begin with

a particular gene that precipitates systemic autoimmunity

(sometimes unexpectedly) when manipulated genetically

by transgenic overexpression or by targeted mutagenesis.

By contrast, reverse genetic studies begin with a sponta-

neous disease or other phenotype; subsequent linkage

analysis studies based on the observed genotype and

phenotype information lead to the identification of dis-

ease-related intervals and eventually to the culprit genes

within the loci. This review will focus on the genetic

perspectives we have gained so far from forward and

reverse genetic studies of lupus, arthritis, Type I diabetes

and multiple sclerosis (MS), as well as their respective

animal models. In addition, loci identified in rodent stud-

ies have been lined up against loci mapped in human

studies in order to uncover any cross-species homologies.

This information is posted on our website (http://www3.

utsouthwestern.edu/mohan/research_projects_1.html).

Potential lupus genes — clues from forwardgenetic studiesIt is very intriguing to observe that the genetic manipula-

tion of a vast array of molecules with very different

functional properties funnels into just one phenotypic

expression pattern — lupus. By contrast, targeted muta-

tions or transgenic overexpression studies that sponta-

neously precipitate autoimmune diabetes, arthritis or

encephalomyelitis are virtually non-existent. The reason

for this striking difference is not yet clear, but it may

relate to the nature of the autoantigens targeted in the

different diseases. Alternatively, this difference could

reflect the possible existence of a primary immunoglo-

bulin and/or T-cell repertoire skewed towards recogniz-

ing nuclear antigens. Whatever the origin of this

difference, it appears that an elaborate cascade of check-

points has been instituted to thwart the emergence and

activation of nuclear-antigen-reactive lymphocytes. Com-

promising any of these serial checkpoints appears to be

sufficient to engender lupus.

To date, >40 genes have been associated with sponta-

neous lupus development when aberrantly expressed in

mice (reviewed in [1–4]). Despite this apparent complex-

ity, one can readily classify these different players into

at least three well-studied functional categories. One

651

www.current-opinion.com Current Opinion in Immunology 2003, 15:651–659

category consists of molecules that have an impact on the

clearance of apoptotic cells (the accumulation of which

may otherwise fuel nuclear-antigen-driven expansion of

autoreactive lymphocytes), including SAP, CRP, C1q,

Mertk and IgM (color-coded red in Figure 1). The second

category consists of molecules that compromise lympho-

cyte apoptosis, such as FAS, FASL, PTEN, PI3K, Bimand BCL-x (color-coded green in Figure 1), which may act

by thwarting the efficient deletional censoring of self-

reactive B cells and T cells. The third category consists of

molecules that amplify or modulate lymphocyte signaling

and expansion, including CD19, Lyn, Fyn, Cr2, CK2a,

CD22, CD45, TACI, p21, Ptp1c, PDCD1 (PD1) and Blys(color-coded blue in Figure 1), which are expected to

amplify anti-self humoral and cellular immune responses.

It should be pointed out that whereas some of these

molecules primarily affect B cells (e.g. CD19, lyn, etc)

or T-cells (e.g. CD45, p21, etc), others influence the

expansion and activation of myeloid cells as well (e.g.

Ptp-1c, lyn, etc). Most of the genes depicted in Figure 1

have been reviewed previously [1–4]. The latest addi-

tions to this list of genes include C4 [5�], IEX-1 [6��], DAF[7�], PKCd [8��,9��], mertk (also known as c-mer) [10��],TACI [11��], Ro [12��] and Gadd45a [13��]. The observa-

tion that molecules with quite different functional prop-

erties can all lead to lupus development suggests that the

different checkpoints that keep nuclear-antigen-reactive

lymphocytes in check are all equally vulnerable, and that

tight patrolling of each successive checkpoint is abso-

lutely essential to prevent systemic autoimmunity. An

important caveat in interpreting these forward genetic

studies is the potential contribution of ‘background’

genes. Most knockouts so far have been derived on the

129 genetic background and, importantly, it has been

Figure 1

Current Opinion in Immunology

1p

ICAM1

Ptp1c

PKCδ

OPN

Cr2

FasLCRP,SAP

Fcg r2b

CTLA4FLIP

CD45

PD1

Bcl2DAF

Ro

8q

6p,q

2q

1q

13q

2q

Nrf2

Mertk

Bim

10p,q

2q

20p,q

11p

Gadd45a

IL2PIK3R1

4q

1q

Lyn

C1qE2F-2

7q

4p

12q

7p,q

12pCD19

CD22

TGFβ119q

15q

11p,q

Blys

CK2a

19q

16q

1q

11q

15q

3p,q

2 3 41 5 6 7 8 9

P21TNF,H2C4, C3

IEX1

Man2a1

6p,q

19p

2p

18p,q

5q

18p,q

11q

9p,q

10qpTEN

Fas

16p

22q

21q

3q

DNase1

Cbl-b

8q

5p14q

13q

9q

5q

2p

7p

14q

IgM

G2A

22q

2p

17pIL4

TACIAiolos

MCP1

6q

12q

IFNγ

Fyn

18 1911 12 13 14 15 16 1710

Potential lupus genes identified through forward genetic approaches. Depicted are the 19 murine autosomes (bold line, with ticks at 10 cM

intervals) and the corresponding human chromosomes (thin line, with specific genomic segments being labeled in orange lettering, at the head of

each interval). Alignments were drawn from the publicly accessible murine and human genome databases http://www.ensembl.org/Mus_musculus/,

http://www.informatics.jax.org/reports/homologymap/mouse_human.shtml/, http://www.ncbi.nlm.nih.gov/genome/guide/human/, and

http://www.ncbi.nlm.nih.gov/genome/guide/mouse/. Shown molecules in this figure are color-coded according to whether the gene impacts

apoptosis (green), the clearance of apoptotic debris (red), lymphocyte activation (blue), or functions via other mechanisms (black). Excluded from

this figure (and from this review) are genes that can potentially ameliorate lupus, or other forms of autoimmunity, when aberrantly expressed.

652 Autoimmunity

Current Opinion in Immunology 2003, 15:651–659 www.current-opinion.com

demonstrated that the lupus-like phenotypes observed in

some of the reported knockouts may be the product of

129-derived genes [14�,15]. This caveat and related issues

have been thoroughly discussed recently [16�].

It is also intriguing to note that the different genes known

to have a potential impact on systemic autoimmunity are

not randomly scattered across the genome but are

unevenly clustered. It is impressive to observe that a

third of the genes displayed in Figure 1 are clustered

around two genomic stretches — distal mouse chromo-

some 1 (homologous to human chromosome 1q) and

centromeric mouse chromosome 17 (corresponding to

human chromosome 6p). On the one hand, this may

simply reflect the fact that these two ‘hotspots’ in the

genome are richly decked with genes of immunological

importance to begin with. On the other hand, clusters of

polymorphic variants of these genes may have co-evolved

by virtue of some associated selective advantage (e.g.

enhanced immune responsiveness against pathogens).

Irrespective of their origins, these clusters lend support

to the possibility that entire haplotypes (rather than, or in

addition to, individual culprit genes) control susceptibil-

ity to autoimmune diseases.

Reverse genetic studies in lupusThe above findings from forward genetic studies indicate

which genes can predispose to lupus, but do not tell us

which genes actually are responsible for the spontaneous

lupus seen in mice and in humans. To address this,

several reverse genetic studies have been executed in

murine as well as in human autoimmunity. In this

approach one begins with a well-characterized disease

(e.g. lupus in humans, or a murine model of lupus), and

works ‘backwards’ to ascertain the genetic loci respon-

sible for the observed disease or phenotypes. Adopting

this approach, several genome scans have been performed

in large collections of mouse progeny bearing random

assortments of genomic intervals derived from lupus-

prone (e.g. NZB, NZM2410, MRL, BXSB) and ‘normal’

(e.g. B6, Balb/c, C3H, etc) genomes; these mice exhibit a

wide spectrum of lupus-related phenotypes. As summar-

ized in Figure 2, mapping studies of this nature have

pointed to the existence of more than fifty loci predis-

posing to the different phenotypic manifestations of

lupus, including anti-nuclear autoantibodies, glomerulo-

nephritis, splenomegaly, mortality and so on. Most of

these murine loci have recently been reviewed [1–4].

Recent contributions to this expanding list include lupus

susceptibility loci from NZM2328 mice [17], the Swrlseries of SWR-derived lupus-potentiating loci [18�], and

NZW-derived Wbw loci [19�].

Although the murine lupus-susceptibility loci mapped to

date appear to be distributed randomly over all 19 auto-

somes, it is intriguing to note that particular intervals on

four chromosomes appear to have been repeatedly

mapped in several independent studies: telomeric chro-

mosome 1, mid chromosome 4, mid chromosome 7 and

centromeric chromosome 17, as is clear from Figure 2. It is

particularly interesting that this list includes the two

‘hotspots’ implicated by forward genetic studies on chro-

mosomes 1 and 17 (Figure 1). Finally, it should be

pointed out that although most of the disease-suscept-

ibility loci originate from lupus-prone genomes (shown in

colors other than black in Figure 2), some are encoded by

otherwise normal genomes (e.g. Baa1 on chromosome 9,

Lmb1 on chromosome 4 and the Sles loci on chromosomes

3, 4, 9 and 17).

The past few years have also witnessed a spate of reverse

genetic studies in human lupus. Collectively, seven sta-

tistically significant lupus susceptibility loci have been

mapped using genome scans (color-coded red in Figure 2),

as recently reviewed [3,20,21]. In addition, several sug-

gestive loci not quite surpassing the threshold for sig-

nificance (color-coded blue in Figure 2) have also been

implicated in lupus susceptibility in two or more genome

scans. In addition, more detailed studies of phenotyp-

ically stratified lupus patients have led to the uncovering

of loci that confer susceptibility to nephritis [22�], throm-

bocytopenia [23�], hemolytic anemia [24�], associated

rheumatoid arthritis (RA) [25��], neuropsychiatric mani-

festations [26�], or anti-dsDNA antibodies [27�] (color-

coded green in Figure 2).

Aligning the murine and human lupus susceptibility loci

against each other (as depicted in Figure 2) also allows us

to identify any potentially shared genetic elements.

Indeed, six out of the seven significant disease-suscept-

ibility loci mapped in lupus patients do overlap with

syntenic regions of the mouse genome to which murine

lupus has also been mapped. Besides these overlaps,

several additional homologies are readily apparent from

Figure 2. In particular, mouse chromosomes 1 and 7 and

the corresponding human chromosomal intervals appear

to be riddled with a string of lupus susceptibility loci. It is

too premature to say if this co-mapping to similar regions

of the corresponding genomes arises from the fact that the

same culprit genes are involved in both species, or

whether this is simply a coincidence. Finally, a compar-

ison of Figures 1 and 2 reveals that several of the genomic

intervals implicated in these reverse genetic studies also

harbor genes that have been shown to impact lupus

development through forward genetic approaches. Need-

less to say, meticulous efforts aimed at identifying any

structural or functional polymorphisms in these impli-

cated candidate genes are in progress in several different

laboratories.

Lupus genetics: from loci to genesThe identification of loci in murine lupus has paved the

way for congenic strain construction and candidate gene

testing. For example, it is clear that the different non-H2

Genetic underpinnings of autoimmunity Raman and Mohan 653

www.current-opinion.com Current Opinion in Immunology 2003, 15:651–659

loci that confer lupus susceptibility in the NZM2410

model lead to very different component lupus pheno-

types when expressed individually on a normal (C57BL/

6) genetic background, as reviewed in [1–3]. The past

year of research has also shed light on how the epistatic

interaction of several different genetic players (identified

through forward or reverse genetic approaches) may be

required to engender full-blown lupus. These include

the demonstration of epistatic interplay between Sle1and FASlpr [28�], FcRIIB�/� with Sle1 or Yaa [29�], and

Cr2�/� with FASlpr [30�].

Candidate gene testing within the implicated loci is in

progress, as reviewed earlier [1–3], and has recently

uncovered two attractive candidates on mouse chromo-

some 1: Cr2 as a candidate gene for the NZW-derived

lupus susceptibility locus Sle1c, and Ifi 202/203 as a

candidate gene for the NZB-derived autoimmunity sus-

ceptibility locus Nba2. In a similar vein, human lupus

geneticists have examined several potential candidate

genes within the implicated genomic intervals for disease

association in human lupus. Among the genes examined,

several have been shown to bear polymorphisms that are

strongly associated with lupus susceptibility, at least in

some of the studies. These include polymorphisms in

IL-10, TNFa, TNFR2, HLA DR/DQ, FcRIIA, FcRIIIA,

FcRIIIB and PARP, as indicated in Figure 2 and reviewed

elsewhere [20,21]. Very recently, intronic polymorphisms

(which have an impact on the binding of RUNX1 to its

enhancer) in the PDCD-1 gene (also known as PD-1) on

human chromosome 2q has been implicated in lupus in

Nordic families [31��].

Figure 2

Current Opinion in Immunology

1p10p,q

2q

20p,q

4q

1q

7q 19p

16q

1q

22q

2p 9q

5p

14q

13q

5p 16p

22q

21q

3q

6p,q

19p

2p

18p,q 11q

9p,q

10q 17p

Sles2 Sle11/Bxs5

Lbw4

4p

11p

12q

SLE

SLER1

SLEV1

SLE

SLE

Wbw1

Lrdm2

Lprm2

Nwa2

SLE

DR/DQ

TNFaC2/C4 8q

5q

18q

SLE

1p

9p

SLE

SLEFcRIIIAFcRIIAPARP, SLESLE

SLE

SLEB2, PDCD1

SLE

SLED2

IL-10

SLE

8q

2q

1q

13q

2q

6p,q

18q

Swrl1Sle1a,b

Cgnz1Nba2

Bxs2Lbw7Sle8

Bxs3Yaa4Sle9

Bana3 Sle1cAgnz1

Sle10/ Bxs4

Sle7/Bxs1

Sle2Lprm1,Adaz1

Lbw2/sbw2Lmb1/Nba1

Sles3

Nba4 Sle6

Lmb2

Lbw3

Lprm4

SLEB3SLESLE

7p,q

12p

Sle3,YaaLbw5

Lmb3

Nba5

Lrdm1

Bxs6

Nba3

SLEH1SLE

SLE

SLE

19q

15q

11p,qSLE

SLED1Sles4

Baa1

Bana2

11q

15q

3p,q

Sle12

Lmb4

Swrl4

6q

12q Lbw8

Nba2p

7p

14q

Nba

Yaa

Nwa

NbaLrpm3

Swrl2

SLEN1MBL

SLELprm5

Nwa1

Agnz2

YaaBana1

Wbw2

Sles1Lbw1

H2/Sle4

Lbw6

Swrl3

2 3 41 5 6 7 8 9

18 1911 12 13 14 15 16 1710

SLEN2

Reverse genetic studies in murine and human lupus. Human and mouse chromosomes were aligned as described in the legend to Figure 1.

It should be pointed out that there is a one-to-many relationship between the mouse genome and the orthologous human chromosomes at

several positions. At these ambiguous sites, human chromosomal intervals that bear the respective disease susceptibility loci have been selected for

portrayal in this figure. Shown mouse loci (on the left of the chromosomes) were drawn from [1–4,17,18�,19�], and are color-coded according to

whether they originated from NZB (red), NZW (blue), MRL (green), BXSB (brown), SWR (orange) or other strains (black). Shown human SLE loci (on the

right of the chromosomes) were drawn from [20,21,22�–24�,25��,26�,27�], and are color-coded according to whether they were statistically ‘significant’

(red), ‘suggestive’ (blue), or conferred susceptibility to specific component lupus phenotypes (green). Indicated in black are known genes

demonstrated to be associated with human lupus in various studies [3,20,21,31��].

654 Autoimmunity

Current Opinion in Immunology 2003, 15:651–659 www.current-opinion.com

Genetics of diabetesReverse genetic studies in murine diabetes have focused

almost exclusively on the NOD strain, which develops

diabetes spontaneously. Currently, �20 named Idd loci

exist (Figure 3), as reviewed in [32,33]. The original

mapping studies as well as congenic dissection studies

have indicated that different Idd loci may be associated

with the different autoimmune phenotypes exhibited by

the NOD strain [32,33]. As with murine lupus, recent

research has focused on congenic interval narrowing [34],

demonstration of epistatic interactions between disease

loci [35], and candidate gene testing. The Idd3 locus has

previously been fine-mapped, leading to the identifica-

tion of IL-2 as the leading candidate gene, as reviewed in

[2,32,33]. Of special note, a transgenic rescue strategy has

recently been used to demonstrate that b2 microglobulin is

the culprit gene within Idd13 [36]. In this study, Slattery

and colleagues have demonstrated that the introgression

of the NOD b2 Ma allele onto a NOD b2 M�/� back-

ground, precipitated diabetes, whereas NOD mice ren-

dered transgenic for the ‘normal’ b2 Mb allele showed

reduced disease. It is worth noting that such a stringent

transgenic rescue test is yet to be applied to the string of

other candidate genes that have been implicated in

autoimmunity. Additionally, genetic studies of diabetes

in the BB rat model have lead to the identification of a

novel culprit gene, Ian4/Ian5 [37�], whose function is

currently poorly understood. Finally, Eaves et al. have

demonstrated the unusual power and utility of perform-

ing microarray analyses on congenic strains [38��].Clearly, this approach represents an unparalleled tool

for candidate gene analysis and biomarker discovery.

Figure 3

Current Opinion in Immunology

2 3 41 5 6 7 8 9

18 1911 12 13 14 15 16 1710

8q

6p,q

2q

1q

1p10p,q

2q

20p,q

4q

1q

7q 7p,q

12p

19q

11p,q

19p

Cia5

Pgia14

Eae10

Eae16

Eae20

Eae3,Tmevd2

Idd3

Idd10

Idd17

Idd18

4p

12q

16q

1q

11q

15q

3p,q

6q

12q

2p

7p

14q

9q

5p

8q

16p

22q

3q

21q

18p,q 11q

9p,q

10q

IDDM7

IDDM12 IDDM13

IDDM10

IDDM3

IDDM9

IDDM6

IDDM17

IDDM4

MS

MS

MS

MS

MS

MS

5p

18q

5q

MS

RA

RA

RA

RA

RA

IDDM17

11p

15q

Cia9

Pgia1

Eae27

Idd5

Tmevd6

Tmevd9

Cia14

Cia15Cia4

Pgia2

Eae21

Eae8

Idd2

Idd13

Cia2

Pgia13

Idd9

Idd11

RA

MS

Pgia16

Eae26

Tmevd7

Idd15

Cia10

Pgia18

Cia3

Cia6

Idd6

Idd19

Idd20

Tmevd1

MS

MS

RA

Eae4Cia7

Pgia21

Eae12

Eae4

Idd7

Pgia3

Pgia19

IDDM2

MS

MS

Pgia4

Eae14

Eae24

Cia16

Pgia22Pgia5Eae9

Idd2

Cia8

Pgia6

Eae15

Eae17

Tmevp3

Tmevp2

IDDM14,15

IDDM

Eae23

Tmevd5 Idd4,Pgia7

Eae7

Eae22

Eae6a

Eae6b

22q

2p

17p

5q

IDDM11

MS

IDDM16

Cia11

Pgia15

Eae13

Cia10

Idd14

Idd8 Idd12

Tmevd3

Tmevd4

Cia17

10q

14q

13q

MS

RA

RA

Pgia8

Pgia9

Eae2

Tmevd8

Pgia10

Eae11

Pgia17 Idd1,Cia1

Eae1Tmevp1

Eae5

Idd16

Pgia20

IDDM5IDDM8

MS

MS,RA,IDDM1

6p,q

19p

2p

16p

6p,q

Pgia11

Eae25

Eae18

Cia18

IDDM18

MS

MS

RA

Pgia12

Eae19

Cia12

Pgia23

Reverse genetic studies in Type 1 diabetes, RA, MS and their respective animal models. Human and mouse chromosomes were aligned as

described in the legend to Figure 1. It should be pointed out that there is a one-to-many relationship between the mouse genome and the orthologoushuman chromosomes, at several positions. At these ambiguous sites, human chromosomal intervals that bear the respective disease

susceptibility loci have been selected for portrayal in this figure. Shown are the susceptibility loci for murine (Idd1-20) or human (IDDM1-18) diabetes,

marked in red; loci for arthritis (marked in green), either in patients (RA) or in experimentally induced models (Cia1-18 or Pgia1-25); and loci for MS

and for experimentally induced encephalomyelitis (Eae1-27, or Tmevd1-9 or Tmevp1-3), coded in blue. For MS and RA, only disease loci which have

been observed in two or more genome scans are depicted, as detailed elsewhere [46,47�,52–57,58�–62�]. The depicted IDDM loci have been

reviewed earlier [39,40].

Genetic underpinnings of autoimmunity Raman and Mohan 655

www.current-opinion.com Current Opinion in Immunology 2003, 15:651–659

A similar number of genetic loci have also been impli-

cated in human Type-I diabetes, as displayed in

Figure 3 and recently reviewed [2,39,40]. Perhaps the

locus with the strongest impact on disease is IDDM1(insulin-dependent diabetes mellitus), wherein poly-

morphisms in HLA DRB, HLA DQB, and HLA DQAgenes appear to be critical. Likewise, polymorphisms in

the insulin gene appear to be the strongest candidate

within IDDM2. IL-12b has also won ample support as

the leading candidate gene within IDDM18, as recently

reviewed [2], with further support from a recently

reported study in Caucasian American families [41].

Finally, polymorphisms in CTLA4 gene weigh in as

the strongest candidate within IDDM12; very recently,

Howson et al. provided more definitive evidence sup-

porting CTLA4 as a culprit gene in murine diabetes, as

well as in patients with Type 1 diabetes, Graves disease,

and autoimmune hypothyroidism [42��].

Genetics of arthritisAs is evident from Figure 3, genome-wide scans in

induced models of arthritis — collagen-induced arthritis

(CIA) or proteoglycan-induced arthritis (PGIA) — have

uncovered �30 loci (color-coded green in Figure 3), as

reviewed previously [43]. An excellent addition to the

recent literature is a comprehensive mapping study of

CIA and PGIA by Adarichev et al. [44�], which confirms

previous Cia/Pgia loci and uncovers additional loci. In

addition, it highlights the relevance of IL-2/IFN-g pro-

duction and T-cell proliferation to disease development.

Although the genetic identities of most Cia/Pgia loci

remain unknown, it is of special note that Holmberg

et al. [45��] have recently positionally cloned a gene

within Pgia4, a rat arthritis susceptibility QTL; this gene

was Ncf1, which encodes neutrophil cytosolic factor 1, a

component of the NADPH oxidase complex.

Four genome scans have been carried out in patients with

RA [46], including one that was recently completed [47�].Disease loci implicated in at least two genome scans are

displayed in Figure 3, color-coded green. It is encourag-

ing to observe that several of these loci — including loci

on human chromosomes 2q, 8q, 14q, 16p, and 18q —

overlap murine intervals mapped following induction of

Cia or Pgia. Once again, although the culprit genes within

these loci are unknown, associations to polymorphisms

in HLA DR/DQ, TNFR2, ICAM-1, FcR, IFN-g, IL-1b,

IL-1Ra, MMP-1 and MBL genes have been described,

as reviewed recently [46].

Genetics of multiple sclerosisA similar degree of genetic complexity has also been

noted to underlie the pathogenesis of experimentally

induced demyelinating disease in mice (either experi-

mental allergic encephalomyelitis [EAE] or Thieler’s

murine encephalomyelitis virus induced demyelination

[TMEVD]) [48]; the loci are color-coded blue in Figure 3.

Recent additions to the literature include the demonstra-

tion of additional, sex-specific susceptibility loci for

TMEVD [49], and of loci that affect T-cell subsets in

EAE [50]. In reviewing the genomic positions of the

murine Eae/Tmevd loci, it is intriguing to note that there

is a remarkable coclustering of loci facilitating EAE or

TMEVD with loci for experimentally induced arthritis

(CIA or PGIA), notably on chromosomes 1, 2, 3, 6, 7, 8, 9,

10, 11, 15, 17, and 18 (Figure 3). It is attractive to postulate

that genes within at least some of these intervals may

serve to facilitate both types of organ-targeted autoim-

munity. Even more intriguing is the observation that

certain genomic intervals (e.g. mid-chromosome 3 and

proximal chromosome 17) confer susceptibility to all four

autoimmune diseases reviewed. It is certainly possible

that the same genes may be having an impact on several

of these diseases. For instance, Teuscher and colleagues

have proposed that sequence polymorphisms in the

chemokines Scya1 (TCA-3), Scya2 (monocyte chemoat-

tractant protein [MCP]-1), and Scya12 (MCP-5) may be

good candidates for Eae7 [51]. It is easy to visualize how

any such functional differences in chemokine expression

may potentially impact end-organ damage in multiple

autoimmune contexts. Only when the culprit genes

within these implicated genomic intervals are identified

will we be able to comprehend the molecular basis for

this co-clustering.

Finally, several genome scans have also been carried out

in patients with MS [52–57,58�–62�]. The identified loci

are indicated in Figure 3, color-coded blue. Although

several genome-wide scans have been conducted, most

scans have failed to reveal significant loci. However, the

HLA locus at 6p21 has been confirmed by several scans.

All loci depicted in Figure 3 have been observed in two or

more genome scans. The responsible culprit genes har-

bored within these loci await elucidation.

ConclusionsThe field of autoimmunity genetics is currently in a rapid

state of flux. As is clear from Figures 2 and 3, >100

autoimmunity loci have been implicated in mice, and

similar numbers have been uncovered in humans. So far,

only a handful of the culprit genes within these impli-

cated loci have been identified. Thanks to the sequencing

of the human and murine genomes, the list of genetic

suspects within any of the implicated intervals is truly

enormous. Over the coming years, as the implicated

intervals becoming progressively whittled down, and as

autoimmunity genes become painstakingly unmasked,

the molecular blueprint for autoimmunity will slowly

but surely be unveiled.

AcknowledgementsWork in the authors’ laboratory is funded by grants from the NIH, TheLupus Research Institute, and the Arthritis Foundation. CM is a recipient ofthe Robert Wood Johnson Jr. Arthritis Investigator Award. UdhayNandagopal’s contribution towards figure preparation is greatly appreciated.

656 Autoimmunity

Current Opinion in Immunology 2003, 15:651–659 www.current-opinion.com

References and recommended readingPapers of particular interest, published within the annual period ofreview, have been highlighted as:

� of special interest��of outstanding interest

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www.current-opinion.com Current Opinion in Immunology 2003, 15:651–659

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27.�

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50. Karlsson J, Zhao X, Lonskaya I, Neptin M, Holmdahl R,Andersson A: Novel quantitative trait loci controllingdevelopment of experimental autoimmune encephalomyelitisand proportion of lymphocyte subpopulations. J Immunol 2003,170:1019-1026.

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56. Coraddu F, Sawcer S, D’Alfonso S, Lai M, Hensiek A, Solla E,Broadley S, Mancosu C, Pugliatti M, Marrosu MG, Compston A:A genome screen for multiple sclerosis in Sardinian multiplexfamilies. Eur J Hum Genet 2001, 9:621-626.

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58.�

Ban M, Stewart GJ, Bennetts BH, Heard R, Simmons R,Maranian M, Compston A, Sawcer SJ: A genome screen forlinkage in Australian sibling-pairs with multiple sclerosis.Genes Immun 2002, 3:464-469.

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59.�

Akesson E, Oturai A, Berg J, Fredrikson S, Andersen O, Harbo HF,Laaksonen M, Myhr KM, Nyland HI, Ryder LP et al.: A genome-wide screen for linkage in Nordic sib-pairs with multiplesclerosis. Genes Immun 2002, 3:279-285.

This recently completed genome scan in MS offers confirmation fordisease susceptibility loci on human chromosome 10p12-13, 6q21 and16p13, backing up evidence from other studies [52–54,56,57].

60.�

Sawcer S, Maranian M, Setakis E, Curwen V, Akesson E, Hensiek A,Coraddu F, Roxburgh R, Sawcer D, Gray J et al.: A whole genomescreen for linkage disequilibrium in multiple sclerosis confirmsdisease associations with regions previously linked tosusceptibility. Brain 2002, 125:1337-1347.

This recently completed genome scan in MS offers confirmation fordisease susceptibility loci on human chromosome 6p21, 17q, 19q and1p, backing up evidence from other studies [52–55].

61.�

Goedde R, Sawcer S, Boehringer S, Miterski B, Sindern E,Haupts M, Schimrigk S, Compston A, Epplen JT: A genome screenfor linkage disequilibrium in HLA-DRB1]15-positive Germanswith multiple sclerosis based on 4666 microsatellite markers.Hum Genet 2002, 111:270-277.

This recently completed genome screen in MS in HLA-DRB1-positivepatients reveals 158 markers to be associated significantly to MS andanother 87 markers to be nominally associated. This screen offersconfirmation for disease susceptibility loci on human chromosome 1p,2p, 6p21, 17q21, 19q, and possibly, several additional regions, backingup evidence from other studies [52,55–57].

62.�

Haines JL, Bradford Y, Garcia ME, Reed AD, Neumeister E,Pericak-Vance MA, Rimmler JB, Menold MM, Martin ER,Oksenberg JR et al.: Multiple susceptibility loci for multiplesclerosis. Hum Mol Genet 2002, 11:2251-2256.

This recently completed genome scan in MS offers confirmation ofdisease susceptibility loci on human chromosome 6p21, 6q27, 12q23-24, 16p13 and 19q13, backing up evidence from other studies [52–54].

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