REVIEWA modular theory of autoimmunity
Junichiro Irie and William M. Ridgway
Division of Rheumatology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA(Received for publication on January 6, 2005)(Revised for publication on March 11, 2005)(Accepted for publication on May 19, 2005)

Abstract. The traditional overarching concept of disease pathogenesis entails the natural history of
disease, i.e. the concept that any disease is a uniﬁed entity from beginning to termination. The conceptof the natural history of disease encourages researchers and clinicians alike to conceptualize all clinicalsigns and symptoms in a patient as manifestations of a single disease process. Our experiences indissecting the genetic control of autoimmune diseases and autoimmune phenotypes suggest that for
many autoimmune processes, an alternative conceptual framework may be more useful. We term thisapproach a ‘‘modular’’ theory of autoimmunity. ‘‘Modules’’ are distinct, genetically controlled clinicalor pathological phenotypes which can interact to construct a disease process. Modules may interact
additively, synergistically, or antagonistically in any given individual. Multiple modules can coexist andproduce unique disease phenotypes. We illustrate this concept with examples from the murine autoimmune model of type one diabetes, the nonobese diabetic (NOD) mouse. (Keio J Med 54 (3): 121–
126, September 2005)
Key words: autoimmunity, genetics, nonobese diabetic mouse, T cell

The concept of a uniﬁed disease process is deeply
engrained in medical teaching and practice. The idea ofthe ‘‘natural history of disease’’ implies that all pathological manifestations in a particular patient arise as aresult of a logical unfolding of biological/biochemical
events in that individual’s genetic and environmental
makeup (Fig. 1). Of course patients may have several
different diseases, but conceptually they are often nonoverlapping. This disease model is well suited to disease
processes such as coronary artery disease. Rheumatological practice, however, is quite different. In Rheumatology a large percentage of patients are classiﬁed as‘‘undifferentiated connective tissue disease’’ or ‘‘overlap syndrome’’. Often, however, the idea is that the true
natural history of the disease in such patients simply has
not yet manifested itself completely, or, that the physician has not yet understood what is in fact an underlying uniﬁed disease process. In either case the fundamental concept is that there is a natural history of
disease in any given patient which fully explains theclinical manifestations over time. Another common
scenario in Rheumatology involves patients who manifest more than one autoimmune disease, such as Pri-

mary Biliary Cirrhosis and type one diabetes (T1D).
A related ﬁnding is extended kindreds manifesting several disparate autoimmune conditions at greater than
expected rates compared to the population at large. In
this scenario, the patient may have Rheumatoid Arthritis, the patient’s aunt may have T1D, and a cousin
may be antinuclear antibody (ANA) positive. Clearly,
genetic factors play a role in such kindreds, but thenature of the genetic inﬂuences have until recently
been obscure.
Our laboratory has spent several years dissecting
the genetic control of spontaneous murine autoimmune
phenotypes and clinical syndromes in the nonobese
diabetic (NOD) mouse. These studies have revealeda different conception of disease which may better represent some autoimmune processes than a ‘‘natural
history’’ of disease. We have found clear evidence that
individual clinical and pathological phenotypes exist
which are genetically controlled and may combine inmultiple different ways to create different autoimmune
syndromes. We term this a ‘‘modular’’ theory of autoimmunity (Fig. 2). The features of component ‘‘modules’’ in autoimmune syndromes are as follows: 1) A

Reprint requests to: Dr. William M. Ridgway, S725 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261, e-mail:ridgway2@pitt.edu
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Fig. 1 The traditional concept of the ‘‘Natural history of autoimmune disease’’. All manifestations of pathology in a patient are
regarded as explained by a single disease concept, represented by thecircular limit around the process. The disease ‘‘unfolds’’ in orderly
fashion over time, as represented by the downward direction of thearrows. A classical representation of the autoimmune disease process
is shown.

module is a distinct clinical or pathological phenotype
which, in relation to other modular phenotypes, may
be additive, independent, or antagonistic. 2) Whilemodules are objective clinical/pathological features of adisease process; the characterization of how modules
relate to each other, on the other hand, is the intellectual creation of the scientist. This means that modules
can be detected and quantitated in patients even without an overarching concept of the disease process inthat patient. 3) Each module is in principal geneticallycontrolled. In other words, environmental triggers of
autoimmunity are not considered in the model; therefore a modular characterization of a process involves
outlining the complete genetically mediated predisposition of an individual to disease. While genetically controlled responses to environmental stimuli are likely
modular, the discovery of such triggers is not a part ofthe modular characterization of the autoimmune process. 4) No disease related module is both necessary
and sufﬁcient for a disease process. In fact, some modules can be described which are neither necessary nor
sufﬁcient for the disease process. 5) Modules which areneither necessary nor sufﬁcient for a disease process
are not therefore irrelevant, but act as disease severity
modiﬁers.
The last two properties of modules, for medical scientists raised on the concept of ‘‘one gene, one disease’’(e.g. sickle cell anemia1) or experienced in the characterization of knock-out phenotypes, requires someelaboration. The familiar Mendelian concept of disease
traces the entire disease pathogenesis to deletions or
mutations in a single gene. Such a characterization ofIrie J and Ridgway WM: Genetic control of autoimmunity

Fig. 2 A ‘‘Modular’’ theory of autoimmunity in the nonobese diabetic (NOD) mice. This ﬁgure shows a ‘‘modular’’ description of thetype one diabetes (T1D) disease process in the NOD mice. Each
module, represented by a two-tiered rectangle, is an independent,
genetically controlled clinical or pathological phenotype. The top tierof each rectangle describes the phenotype, the bottom tier describes
the genetic control (when known). Modules may be independent,
additive, or antagonistic (see text). Arrows represent the scientiﬁchypotheses ‘‘connecting’’ the modules, however modules exist in
patients independent of any known theory connecting them into a
coherent ‘‘disease process’’ (these modules, for example ‘‘Autoab’’,
aren’t connected to other ones with arrows, yet are nonetheless present in the disease process). Modules can be identiﬁed and studied inany patient regardless of a ‘‘disease diagnosis’’.
Abbreviations: ‘‘c1’’, ‘‘c3’’ etc. describe the chromosomal location
known to control the phenotypes. ‘‘Tcr rep’’ ¼ the T cell receptor
repertoire in a patient. ‘‘CD4 Reg’’ ¼ CD4þ regulatory cell development. ‘‘Autoab’’ ¼ autoantibody production. ‘‘Th bias’’ ¼ intrinsic
property of CD4þ T helper cells (Th cells) to produce a skewed cytokine response (for example see reference 31). ‘‘NK T fxn’’ ¼ intrinsic
cytokine response of NK T cells after stimulation. ‘‘Inc CD4’’ refers to
an increased CD4 : CD8 T cell ratio in the peripheral blood T cell
repertoire (see reference 32). ‘‘Homing’’ refers to the capability ofpathological T cells to enter a target organ; for example NOD.Idd3/5
mice show decreased insulitis which may be the result of changes in T
cell homing (see text). ‘‘?’’ ¼ refers to an unknown phenotype or an
unknown genetic location.

the hemoglobin gene in sickle cell anemia ushered in
the era of molecular medicine. Many common diseases,
and in particular many common autoimmune diseases,
however, do not follow simple Mendelian genetics andare not the result of ‘‘knock out’’ mutations in single
genes.2,3 Rather, many autoimmune diseases are characterized by multigenicity in which causative genes may
actually be functional, common allelic variants in a deleterious mixture. In the examples we will be demonstrating, multigenic origin precludes a singular ‘‘modular’’ phenotype from explaining the disease process.
Hence, in contrast to many genetic studies, in the ge-Keio J Med 2005; 54 (3): 121–126

netic study of modules no single module will be bothnecessary and sufﬁcient. Even harder to accept is thenotion that some modules may be neither necessary
nor sufﬁcient to the disease process. The immediate
tendency is to conclude that such pathological processes
would therefore be irrelevant. Many examples exist,
however, to demonstrate that modules which are neither necessary nor sufﬁcient for a disease can act as
disease severity modiﬁers. We will illustrate these concepts in the NOD mouse model of T1D.
The NOD mouse is a spontaneous, genetically complex model of T1D.4,5 Starting around 3 weeks of age,
NOD mice develop lymphocytes invading the pancreatic islets (‘‘insulitis’’), although they do not immediately cause destruction of tissue.6 Around 12–16 weeks,pancreatic islet destruction begins, with subsequentglycosuria and clinical diabetes. It has been shown that
T cells are key mediators of the disease process, sinceCD4þ T cells can transfer the disease into naive NOD
and NOD-scid recipients.7 In addition, the NOD MHC
class II molecule (I-A g7 ) is unique, bearing a strong
structural resemblance to a human MHC associatedwith T1D.8 The I-A g7 molecule was shown to possess a
non-aspartic residue at position 57 and probably acts
both by selecting an autoreactive T cell repertoire andby presenting autoantigens to T cells.9 Finally, anti-T
cell therapies such as anti-CD3 can prevent diabetes
and reverse established disease in NOD mice.10 Not
only T cells, but most immune cells have been implicated in the NOD autoreactive process.
The NOD mouse model is a prototype for the characterization of a genetically complex autoimmune disease. The ﬁrst genome scan of NOD mice was performed almost 15 years ago, and demonstrated thatmultiple recessive loci, termed ‘‘insulin dependent diabetes’’ (Idd) loci, were linked to diabetes resistance orsusceptibility.11 At present at least 20 genes are thought
to play a role in this complex, multigenic process.12 The
strongest genetic contribution is from the MHC class II
molecule, I-A g7 , however it is important to note thateven two copies of this powerful gene are insufﬁcient tomediate diabetes when placed on a non-autoimmune
background: the congenic mouse B6.G7, which has twocopies of the NOD MHC class II molecule bred onto
the non-disease associated B6 background, does notdevelop diabetes.13 Therefore while substitution ofother MHC class II molecules can prevent diabetes,(indicating that I-A g7 is necessary for disease), it is notboth necessary and sufﬁcient.
Following the genome scan identiﬁcation of areas
linked to disease, the next step was construction of Idd
congenic mice, which are mice bred to contain a predominant NOD (disease related) genetic backgroundwith a B6 resistance (Idd) locus bred onto it. These
congenic mice show decreased susceptibility to diabe-

123tes, conﬁrming that the gene or genes whose B6 alleles
were resistant to disease were ‘‘captured’’ in the congenic intervals.12 The congenic genetic intervals are
initially quite large (>40 megabases), so the next step
to isolating the gene(s) involved is called ‘‘congenic
mapping’’, whereby mice are progressively bred so thatthe genetic interval is narrowed. This approach has led
to the identiﬁcation of several ‘‘candidate’’ genes in theintervals.14–19 An accompanying step is the identiﬁcation of unique immunophenotypes associated with theunique genotypic structure of these mice. The rest of
this article will describe our results with several of thesemice and show how they illustrate a modular concept of
autoimmunity.
Our ﬁrst example concerns genetic control of autoantibody production. Antinuclear antibodies are considered a hallmark of autoimmunity, in particularconnective tissue diseases such as Systemic Lupus
Erythematosis (SLE). Anti-Sm antibodies, directedagainst the spliceosome complex, are considered very
speciﬁc for human SLE.20 In our colony, neither NOD,
B6 nor B6.G7 mice develop ANA or anti-Sm antibodies. When we checked NOD.Idd9 congenic mice,(which are mice with mostly an NOD genetic background except for B6 ‘‘resistance’’ Idd loci on chromosome 4 (‘‘c4’’); the ‘‘Idd9’’ simply means this was theninth Idd locus identiﬁed in the literature) however,they developed both ANA and anti-Sm antibodies.21
Only 2% of NOD.Idd9 congenic mice develop diabetes.15 Since B6 and B6.G7 mice, which have the genetic
region on chromosome four found in NOD.Idd9 mice,
don’t develop autoantibodies, it is clear that the c4
region must interact with the NOD genetic backgroundto generate autoantibodies. The process is speciﬁc to
the c4 congenic mice, since NOD.Idd3/5 mice (with Idd
loci on chromosomes 1 and 3) which also have a low(2%) prevalence of diabetes, do not generate theseautoantibodies. Nor do NOD.Idd3/10/18 mice (with a
B6 genetic interval from chromosome three (‘‘c3’’)). In
contrast, a congenic mouse with both the c3 and c4
intervals, which we described as NOD.c3c4 mice, develop no autoimmune diabetes but also demonstrated
both ANA and anti-Sm antibodies.21
Our description of autoantibody production in NOD
congenic strains conﬁrms similar data from other labs
looking at anti-insulin autoantibody (IAA) productionin the same set of mice.22 This paper demonstrates that
NOD.Idd3/5 and NOD.Idd3/10/18 mice had low prevalence of IAA production, while NOD.Idd9 mice had ahigh prevalence. Remarkably, however, the NOD.Idd9
mice, despite the high prevalence of autoantibodies,
have a low prevalence of disease; conversely mice
without the autoantibodies developed diabetes.22 This
therefore has the hallmark of one of the features of amodular phenotype: autoantibodies which are geneti-

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cally controlled in expression, but neither necessary nor
sufﬁcient for disease onset. If the phenotype of IAA
production is neither necessary nor sufﬁcient for T1D,
is it therefore irrelevant? We would argue not. Rather,
we suggest that such genetically controlled ‘‘modules’’can ‘‘stack’’ with other modules and make a disease
process worse, i.e. they can act as disease modiﬁers.
The next module we will describe is ‘‘insulitis’’,i.e. the accumulation of lymphocytes in the pancreatic
islets. It is hard to imagine diabetes occurring in theabsolute absence of insulitis, so it is tempting to describe it as a ‘‘necessary’’ component of the autoimmune
process. Is it also sufﬁcient? And is it genetically controlled? These answers are known. The NOD.Idd9
mouse described above has a very low (2%) prevalenceof diabetes. Surprisingly, however, it has a very highgrade insulitis.16 Therefore, insulitis can occur without
progression to diabetes, and is not therefore sufﬁcientfor diabetes. Genetic control of insulitis has also beenclearly demonstrated: Loci on chromosomes one andthree clearly can act to allow or prevent insulitis depending on genetic background.16,23 NOD.Idd3/5 mice,for example, show marked suppression of insulitis.14
We have shown that NOD.Idd3/10/18 mice, in contrast,
not only show decreased insulitis, but they develop
lymphocytic inﬁltrates into the liver, in the absenceof ANA or anti-Sm autoantibodies. It appears that in
NOD.Idd3/10/18 mice, the trafﬁcking of lymphocytes
to the liver and pancreas is mutually exclusive or
antagonistic.21
The description of high grade insulitis in NOD.Idd9
mice, along with ANA and anti-Sm autoantibodies,clearly illustrates an ‘‘additive’’ feature of the two modules, i.e. insulitis and anti-Sm antibodies can exist in
the same individual. The question arises as to what‘‘disease’’ the NOD.Idd9 mice have. We would argue
they have no particular classically deﬁned autoimmune
disease, but a modular disease composed of additive
autoimmune modules. A rheumatologist might diagnose these mice with SLE. Two of one hundred such
mice, however, develop autoimmune diabetes, and mostof them develop insulitis, not ‘‘normal’’ features ofSLE.
Our next example of an immunomodule concerns
NK (‘‘Natural Killer’’) T cell function. NK T cells are
lymphocytes expressing both T cell and NK T cellmarkers. They characteristically rapidly express immunomodulatory cytokines after anti-CD3 stimulationin vivo.24 A large number of publications described afunctional NK T cell defect as causative in NOD diabetes. Gombert et al. demonstrated decreased NK T
cell numbers with decreased IL-4 production.25 Hammond et al. showed that NK T cells form another strain
could correct the defect and prevent diabetes.26 NOD
mice constructed with NK T cell transgenes (T cell

Irie J and Ridgway WM: Genetic control of autoimmunity

receptors from NK T cells were overexpressed intransgenic mice) were protected from diabetes. In addition, several groups reported that an NK T cell ligand,alpha-galactosylceramide, prevented diabetes in NOD
mice.27–29 Finally, Yang et al. reported that thymocytes
from AKR mice (a non diabetic strain) did not reconstitute diabetes in NOD-scid mice, but thymocytes from
B-2m (Beta-2 microglobulin, a necessary componentof the MHC class I molecule. In absence of the class I
molecule NK T cells cannot develop) deﬁcient AKR
mice did cause diabetes, seemingly strong evidence thatan NK T cell deﬁciency is both necessary and sufﬁcientfor diabetes in NOD mice.30 We examined NK T cellfunction in NOD congenic mice. We conﬁrmed thatNOD mice, compared to MHC class II matched B6.G7
mice, had a profoundly defective cytokine response
to intravenous anti-CD3, characterized by defective IL4 production. Surprisingly, however, NOD.Idd3/5 mice
showed the same functional defect, despite a 40 folddecreased diabetes incidence compared to NOD mice
(unpublished observations, Ridgway lab). Therefore,
the NOD NK T cell functional defect is neither necessary nor sufﬁcient for diabetes, just as in the case withthe autoantibodies described above. Again, we would
not therefore conclude that this phenotype is irrelevant
to autoimmunity. Rather, NK T cell cytokine defects
may act as a disease modifying module, which could
enhance an autoimmune process in the context of otherautoimmune modules. It is likely that the NK T cell
defect is not operative in NOD.Idd3/5 mice due to theabsence of the insulitis module described above.
We have described several independent, additive,
autoimmune related, genetically controlled modules.
We would like to conclude by illustrating an ‘‘epistatic’’effect of combining modules, i.e. the unexpected manifestation of new phenotypes when two sets of genes are
combined. We have already shown that NOD.c4 (Idd9)
mice develop ANAs, anti-Sm antibodies, and insulitis.
NOD.c3 (Idd3/10/18) mice show suppression of insulitis
and no autoantibodies, but trafﬁcking of lymphocytes tothe liver. What would happen if these genotypes werecombined? The answer is dramatic. These mice, termedby us NOD.c3c4 to indicate that they had ‘‘protective’’(for diabetes) loci from both chromosome three andfour, were totally protected from diabetes and showed
no insulitis. About 90% of these mice, however, developed an eventually fatal autoimmune biliary disease.21
The NOD.c3c4 mice developed ANA and Anti-Sm
antibodies, as did the NOD.c4 mice. In addition, however, they developed novel autoantibodies not seen in
the NOD.c4 nor any other NOD congenic mice.21 The
NOD.c3 mice had shown liver inﬁltrating lymphocytes
but no clear disease process. The NOD.c3c4 mice,
however, developed progressive lymphocytic biliary inﬁltration with biliary epithelial disturbance and hep-

Keio J Med 2005; 54 (3): 121–126

atomegaly, and the mice eventually die from biliary
obstruction.
NOD.c3 mice showed liver inﬁltrates but no overall
disease process; NOD.c4 mice showed autoantibodies
but no overt disease process. Combining these genetic
segments lead to a novel ‘‘emergent’’ liver disease
process and novel autoantibody production in the
NOD.c3c4 mice. The interaction of homozygous B6
c3 and c4 intervals with the rest of the NOD genome
is necessary for the disease, as shown by breeding
NOD.c3c4 mice to either NOD or B6 (making ‘‘F1’’
mice which were heterozygous at some loci). (NOD) (NOD.c3c4)F1 mice, surprisingly, had no liver disease,but developed diabetes. Therefore heterozygous c3c4
intervals interacting with a homozygous NOD background were not sufﬁcient to prevent diabetes nor mediate liver disease. (NOD.c3c4)  (B6.G7)F1 mice, incontrast, expressed homozygous B6 intervals across thec3c4 region, but developed no diabetes, no liver disease, no antibodies, and no insulitis; in fact these miceappeared perfectly healthy.21 These breeding experiments clearly illustrate the importance of interactions
between the disease related genes and the rest of the
genome in the disease process.
The congenic mice described in this article are all
remarkably genetically similar, with 90–99% NOD genetic background and small B6 genetic intervals crossed
in. In a sense, therefore, they represent a kindred ofgenetically closely related individuals. As such they
demonstrate how profoundly sensitive the expression of
autoimmune phenotypes can be to small changes ingenetic composition. We have shown that mice whichhave no disease in the classical sense of the word canmanifest genetically controlled ‘‘modules’’ which, if
combined with other modules by mating, can interact
to produce novel autoimmune syndromes. Alternately,
mice manifesting no disease can carry several disease
related ‘‘modules’’ which, in the ‘‘wrong’’ mating cross,could erupt into profound autoimmunity. For example,
NOD.Idd9 mice show abnormal lymphocyte trafﬁcking
to the pancreas and autoantibodies; NOD.Idd3/5 mice
have profound NK T cell defects; both mice have thedisease related MHC class II molecule, but neither ofthem develop an overt classical disease process.
Human clinical autoimmunity demonstrates characteristics which could be explained by the ‘‘modular’’theory presented here. Autoimmunity of different forms
in an extended family could reﬂect segregation of different modules in different combinations. Patients withbizarre mixtures of autoimmune features, in particular‘‘undifferentiated’’ connective tissue diseases or ‘‘overlap’’ syndromes, likely represent patients with deleterious mixtures of autoimmune related modules. The
proper approach to understanding these patients in human autoimmune disease likely is to focus on ‘‘subset-

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ting’’ of patients according to immune phenotypes(or modules) regardless of their ‘‘disease diagnosis’’. A
modular approach to human autoimmunity will provide
a more ﬂexible paradigm for understanding the diversity of autoimmune expression and for eventually dissecting the genetic control of human autoimmunity.
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