Autoimmunity Reviews 8 (2009) 682–686

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Autoimmunity Reviews
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev

Infection and type 1 diabetes mellitus — A two edged sword?

Elad Goldberg a, Ilan Krause b,c,⁎
a
Infectious Diseases Unit, Rabin Medical Center, Beilinson Hospital, Israel
b
Department of Medicine E, Rabin Medical Center, Beilinson Hospital, Israel
c
Sackler Faculty of Medicine, Tel-Aviv University, Israel

a r t i c l e i n f o a b s t r a c t

Article history: Infection by various viral and bacterial pathogens has long been proposed as one of the
Received 23 January 2009 etiologies of autoimmune diabetes. Many theories, ranging from direct cytolysis of pancreatic
Accepted 9 February 2009 islet cells to immunological processes such as antigen mimicry and polyclonal lymphocyte
Available online 13 February 2009
activation, tried to explain the epidemiological correlation between infections and diabetes,
supported by information from human and animal studies. However, a direct correlation and
Keywords:
exact mechanism continue to elude investigators due to scarce and conflicting data.
Type 1 diabetes
Infections
Interestingly, there is also data to support an opposite role for infection in the development
Viruses of type 1 diabetes, as several pathogens demonstrated a protective effect from this disease. This
Bacteria article reviews the current data available from clinical studies and animal models, while trying
Autoimmunity to explain the different mechanisms underlying these findings.
© 2009 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 682
2. Infection as a possible trigger of T1DM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683
2.1. Viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683
2.1.1. Enteroviruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683
2.1.2. Cytomegalovirus (CMV) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683
2.1.3. Other viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683
2.2. Other pathogens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 684
3. Infections protecting from type 1 DM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 684
4. Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 685
Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 685
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 685

1. Introduction environmental triggers involved in the pathogenesis of the

The autoimmune etiology of type 1 diabetes mellitus
(T1DM) has been studied extensively for many years. The
immunological mechanisms leading to the destruction of
pancreatic β-cells are clearer today, as are the genetic factors
responsible for host susceptibility [1]. However, the exact
⁎ Corresponding author. Department of Medicine E, Rabin Medical Center,
Beilinson Campus, Petach Tikva 49100, Israel.
E-mail address: ikrause@post.tau.ac.il (I. Krause).
disease are yet to be determined. Identifying these triggers
has become of utmost importance as the incidence of T1DM is
increasing [2]. Different environmental factors are implicated
in the etiology of autoimmune disease, and among them the
role of infection is a long standing assumption studied by
numerous investigators [3]. Three main mechanisms explain-
ing this relation were proposed: activation of polyclonal
lymphocytes by the infection, protein sequences of the
infecting pathogen mimicking autoantigens, and increased
immunogenicity due to target organ inflammation, inducing

1568-9972/$ – see front matter © 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.autrev.2009.02.017
 E. Goldberg, I. Krause / Autoimmunity Reviews 8 (2009) 682–686
an autoimmune response. All three mechanisms result in the
induction of autoantibodies and other processes recognized
in the pathogenesis of autoimmune diseases [4]. However, it
should be noted that direct causal relation between an
infecting agent and an autoimmune disease has not yet
been solidly confirmed.
Interestingly, research of an opposite relation between
infection and autoimmune diseases has gained momentum.
This originated in the “hygiene theory”, noting that allergic
and autoimmune diseases increased in frequency in the
developed countries while infectious diseases became rarer,
suggesting a protective effect of infection in relation to
autoimmune diseases [5]. Most of the data on this relation
comes from epidemiological studies correlating the presence
of antibodies to certain pathogens and the incidence of
autoimmune disease [6]. Further data is available from animal
models.
Infection as an environmental trigger for T1DM has been
studied extensively, especially in laboratory setting and
animal models, less so in clinical trials. Data on the effect of
different infections on β-cells and the development of
autoimmune diabetes is growing, but no major conclusions
have been made yet. In this review we will attempt to
organize and present the existing data and discuss its
implications.
2. Infection as a possible trigger of T1DM
As specified above, the role of infection in the develop-
ment of T1DM has been reported both in animal models and
in humans. As aforementioned, 3 major mechanisms were
suggested as an explanation for this role:
1) Activation of polyclonal B or T cells by the infecting agent,
thereby triggering production of different autoantibodies,
including islet-cell antibodies [7]. Data supporting this
mechanism is, however, scarce and inconclusive.
2) Mimicking of autoantigens by pathogen proteins. This
mechanism has been implicated in autoimmune diseases
such as multiple sclerosis and Guillaine Barré syndrome. It
was also proposed for T1DM, with viral proteins mimick-
ing autoantigens such as GAD65 and inducing T-cell
reaction [8]. Attempts to reproduce this reaction were
not always successful, casting doubt on this mechanism.
3) Infection induced inflammation increasing the expression
of molecules which participate in the process of autoanti-
gen recognition by T-cells. This phenomenon was sup-
ported in several animal model studies [9], but was not
directly demonstrated in human studies.
The bulk of the data in T1DM patients concerns different viral
infections, while other pathogens are reported sporadically.
2.1. Viruses
Viral infections have been implicated in the pathogenesis
of T1DM as early as the 1970s. Several theories of pathogen-
esis were raised, according to the different type of virus and
its effects on pancreatic tissue and the immune system. One
such theory is that of direct infection and lysis of pancreatic β-
cells. This is supported by different case reports in humans,
and in animal models as well. However, other reports failed to
683
identify viral infection in the pancreatic tissue of T1DM
patients. Indirect effects of viral infections on various
immunological mechanisms have also been described for
different viruses in humans and animals.
2.1.1. Enteroviruses
First evidence for the relation between enteroviruses and
T1DM relied on antibody assays, demonstrating increased
prevalence of enteroviral IgM in the sera of T1DM patients
[10] and in mothers to children with T1DM compared with
controls [11], although not all reports reproduced these
findings. Subsequently, these findings were strengthened by
newer molecular methods which detected enteroviral RNA in
the blood of T1DM patients. However, the attempts to
determine the exact mechanism underlying the correlation
between enteroviruses and T1DM met with difficulties.
Different enteroviruses are capable of directly destroying
human pancreatic islet cells in vivo. However, it was shown in
animal models that infection of the cells may be dependent
on the presence of pre-existing inflammation [12]. Further-
more, genetic factors also affect the ability of enteroviruses
and other viruses to damage islet cells and induce diabetes
[13]. Other studies in animal models did not demonstrate a
direct effect of enteroviruses on islet cells, but an indirect
autoimmune response probably induced by the virus [14].
Therefore, enteroviruses may play a significant role in the
development of T1DM in association with immunologic and
genetic host factors.
2.1.2. Cytomegalovirus (CMV)
CMV has been implicated as a trigger for the development
of T1DM in several case reports and following demonstration
of a correlation between viral genome identified in leucocytes
and autoantibodies to islet and β-cells in T1DM patients [15].
However, several other reports cast doubt on this relation, as
positive serology for CMV was not associated with develop-
ment of T1DM or of β-cell autoantibodies. Animal models
support the role of CMV in the development of T1DM, either
through activation of macrophages and proliferation of
autoreactive T-cells [16] or through induction of islet-cell
specific autoantibodies [17]. The search for the exact
mechanism involving CMV infection and T1DM is still under
investigation both in clinical and laboratory studies. More
recently, the effect of CMV on different complications in solid
organ transplanted patients, including post-transplantation
diabetes, has been studied extensively. The incidence of new
onset diabetes is higher among transplanted patients with
asymptomatic CMV infection [18], but the exact role of the
virus in this relation is still investigated.
2.1.3. Other viruses
Several other viruses were investigated as potential
triggers for T1DM. Among the most recently investigated are
rotaviruses, a major cause of diarrhea among the pediatric
population. Epidemiological data demonstrated a correlation
between rotavirus infection and first appearance of antibodies
to insulin and islet-cell antigens [19]. It should be noted that
this correlation was not observed in other reports, specifically
in T1DM genetically susceptible children [20]. Results from
several studies in animal models remain inconclusive; how-
ever it appears that timing of the infection in relation to
684 E. Goldberg, I. Krause / Autoimmunity Reviews 8 (2009) 682–686
existing inflammation may determine the effect of the virus on
the development of T1DM [21].
Two other viruses implicated as causing T1DM are rubella
and mumps. Epidemiological data demonstrated an increased
rate of T1DM among children with congenital rubella or
mumps infection. Furthermore, increase in the incidence of
autoimmune diabetes appeared to have been restrained
following the introduction of the measles–mumps–rubella
(MMR) vaccine [22]. However, the incidence of T1DM
resumed its upward trend since then. Both viruses can infect
human β-cells, but do not induce their destruction [23,24].
Rubella is known to mimic antigens recognized by T-cells of
diabetic patients [25], while mumps is involved in cytokine
release from human β-cells [26]. Although it is unclear
whether these viruses play a significant role in the pathogen-
esis of T1DM, it appears they are involved in immunologic
processes related to this disease.
Other viruses have been reported as possible cause for
T1DM (parvovirus, encephalomyocarditis virus, influenza,
retroviruses), but data on these pathogens is scant, and no
pathogenetic mechanisms have been established for any of
them.
2.2. Other pathogens
Bacterial infections, although less than viral, have been
investigated as possible triggers for autoimmune diseases,
including T1DM. Bacterial DNA is known to stimulate the
immune system to produce DNA autoantibodies that may
play a role in autoimmune diseases [27]. When addressing
T1DM, the possible mechanisms underlying the effect of
bacteria on the pancreas resemble the ones proposed for
viruses (i.e., direct damage to β-cells, immunological
mechanisms such as antigen mimicry, activation of lympho-
cytes and modification of cytokine activity). A bacterial
mechanism irrelevant to viruses is toxin mediated damage
to the pancreas. This has been observed in animal models
using Streptomyces species and the bafilomycin toxin they
produce. The toxin caused glucose intolerance, reduction in
islet size and β-cells mass [28]. It also caused disruption of the
pancreatic organogenesis in utero, thus accelerating the onset
of diabetes [29]. However, these findings were not consoli-
dated by additional data.
More recently, newer mechanisms of bacterial involve-
ment in T1DM were proposed and investigated. Alterations in
the intestinal microbiota have been shown to affect the
development of diabetes in animal models, and administra-
tion of different antimicrobial agents decreased the incidence
of T1DM in these animals [30]. There is increasing data that
the gut flora is involved in different immunological processes,
including autoimmunity. Different factors, such as the timing
of introduction of different agents to the gut flora and a
possible leak that triggers immunological and autoimmune
responses, have been proposed as explanations for this
phenomenon. However, this mechanism remains elusive as
some of the microbial agents induce protection from diabetes
while others may trigger the disease.
Other bacterial pathogens were also implicated in the
development of T1DM. One of them is Mycobacterium
avium, whose DNA was detected in the peripheral blood of
a large proportion of T1DM patients compared with healthy
controls [31]. Other anecdotal reports exist for bacterial
pathogens such as pertussis and even protozoal pathogens
such as schistosoma, but none of them has so far been
established.
3. Infections protecting from type 1 DM
As mentioned before, there is a correlation between a
decrease in infectious diseases in the developed countries and
a continuous rise in the incidence of T1DM. This is supported
by further epidemiological data demonstrating higher rate of
T1DM in low-crowded households [32] and in first born
children (less exposed to infections in their siblings).
Supporting evidence is available from animal models. It has
been shown that diabetes may be prevented in susceptible
laboratory animals by introduction of mycobacterial cell wall
components [33].
Animal models have been helpful in understanding the
underlying processes of this protective effect. Two proposed
explanations for this effect are homeostatic competition
(infection induced lymphocyte expansion and competition
with other lymphocytes involved in the autoimmune process)
and bystander suppression (suppressive immune response to
infection affects the autoimmune process).
A recently investigated mechanism is the effect of Toll like
receptors (TLRs) on activation of the immune system and
possible regulation of autoimmune responses. TLRs are a
group of receptors recognizing different microbial and fungal
ligands and participating in the immune system response to
infections. It has been shown that TLRs are major contributors
to the protective effect of infection on the development of
diabetes, as shown in diabetes susceptible animals receiving
bacterial extracts.
These findings further clarify the complexity and diversity
of the effects of infection on autoimmune responses and
diseases, specifically T1DM.
One of the first evidence for bacterial protection against
T1DM was the observation that BCG vaccination (prepared
from Mycobacterium bovis) of NOD mice suppresses overt
diabetes [34]. This observation was repeated with M. avium,
which prevented diabetes in NOD mice, although the animals
were resistant to the infection [35]. Another interesting
pathogen which was implicated as a cause for T1DM, but
prevents the disease in animal models is Schistosoma mansoni.
It appears that exposure to antigens of the Schistosoma worm
or eggs modulates immune responses of T-cells and inter-
leukin levels, and thereby prevents T1DM in NOD mice [36].
The most explored protective pathogen in animal models is
the lymphocytic choriomeningitis virus (LCMV), which
prevents the development of T1DM in NOD mice. When
infected with this virus, the mice did not develop lymphocytic
infiltrates of the pancreatic islets (which did appear in
uninfected mice). Furthermore, lymphocytes from infected
animals also prevented T1DM in uninfected mice [37]. This
model has been duplicated in other trials, but clinical data in
humans is lacking. Several other pathogens demonstrated a
protective effect in animals susceptible to diabetes. Salmo-
nellatyphimurium infection has been shown to prevent T1DM
in NOD mice, although the protective mechanism is not clear
[38]. Even the Coxsackie virus which was extensively
investigated as a culprit in T1DM, was shown to produce
 E. Goldberg, I. Krause / Autoimmunity Reviews 8 (2009) 682–686
long term protection from the disease in NOD mice when the
infection precedes the inflammatory process [39]. Another
virus implicated as a trigger for T1DM, Rotavirus, was also
shown to provide protection from development of T1DM in
infant and young adult NOD mice following oral and intra-
peritoneal administration [40].
4. Comments
The relation between infection and T1DM has been
studied for more than 4 decades. Data has been accumulating
both from human studies and animal studies, shedding light
on the different pathogens involved in the etiology of diabetes
and the different mechanisms responsible for this relation. As
the amount of data increases, more pathogens are identified
and additional mechanisms are proposed. However, direct
data linking these pathogens to T1DM is scarce, and there are
conflicting findings that do not enable a full understanding of
the biological pathways behind this correlation. Even more
baffling is the fact that several pathogens, including ones that
are implicated as causing T1DM, seem to provide protection
from this disease under certain conditions.
It is obvious that infectious pathogens, especially viruses,
are involved in biological and immunological processes that
contribute to the development of autoimmune diabetes. It is
also clear that these processes are complex and not yet fully
understood. In order to clarify the role of infection in the
etiology of diabetes, both animal and human studies are direly
required, so that we may keep up with the ever changing
epidemiological picture of infection and autoimmunity.
Take-home messages
• Epidemiological and laboratory findings support the corre-
lation between infections and type 1 diabetes.
• Different viruses, especially enteroviruses, and bacteria are
involved in the etiology of autoimmune diabetes through
immunological processes and direct damage to the pancreas.
• Infectious agents may also be associated with protection
against the development of autoimmune diabetes.
• The timing of the infection and the type of pathogen may
determine the different effect on the immune system, thus
triggering the disease or protecting the host from it.
• The exact mechanisms behind these findings remain
elusive, and necessitate further research.
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Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double-blind, methotrexate-controlled
study of patients with active rheumatoid arthritis

New therapies are under development to improve the efficacy in the treatment of rheumatoid arthritis, monotheparies should
promise to be good enough as traditional ones in the improvement of disease course and symptoms. In a recent study, Cohen SB
et al, (Arthritis and rheumatism 2009;60:335–344) intended to compare the efficacy and safety of pamapimod (a selective
inhibitor of the alpha-isoform of p38 MAP kinase) as monotherapy in comparison with methotrexate (MTX) treatment in adult
patients with active rheumatoid arthritis (RA). Patients in a randomly assigned to 1 of 4 treatment groups and received 12 weeks of
double-blind treatment. One group received MTX (7.5 mg/week with planned escalation to 20 mg/week), and 3 groups received
pamapimod (50, 150, or 300 mg) once daily. The primary efficacy end point was the proportion of patients meeting the American
College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at 12 weeks. Secondary end points included
ACR50 and ACR70 responses, change from baseline in the Disease Activity Score in 28 joints (DAS28), categorical analyses of
DAS28/European League Against Rheumatism response, and change from baseline in each parameter of the ACR core set of
measures. Safety monitoring included recording of adverse events (AEs), laboratory testing, immunology assessments, adminis-
tration of electrocardiograms, and assessment of vital signs. As result, patients assigned to receive MTX and pamapimod had similar
demographics and baseline characteristics. At week 12, fewer patients taking pamapimod had an ACR20 response (23%, 18%, and
31% in the 50-, 150-, and 300-mg groups, respectively) compared with patients taking MTX (45%). Secondary efficacy end points
showed a similar pattern. AEs were typically characterized as mild and included infections, skin disorders, and dizziness.
Pamapimod was generally well tolerated, but the 300-mg dose appeared to be more toxic than either the 2 lower doses or MTX. The
researchers concluded that pamapimod was not as effective as MTX in the treatment of active RA.

Monoarticular corticosteroid injection versus systemic administration in the treatment of rheumatoid arthritis patients: a
randomized double-blind controlled study

Monoarticular corticosteroid injection versus systemic administration in the treatment of rheumatoid arthritis patients is still an
interest are for disccusion. Konai MS, et al. (Clin Exp Rheumatol 2009;27:214–21) intended to compare the efficacy and safety of
intraarticular glucocorticoid injection to its systemic use for treatment of knee synovitis in rheumatoid patients. A randomized
double-blind controlled study was conducted including 60 patients with RA. Patients were randomized to receive either a single
intraarticular knee injection with triamcinolone hexacetonide 60 mg (3 ml) and xylocaine chloride 2% (1 ml) associated to a single
intramuscular injection of 1 ml of xylocaine chloride 2% (IAI group) or 1 ml of xylocaine chloride 2% by intraarticular injection and a
intramuscular injection of triamcinolone acetonide 60 mg (3 ml) and xylocaine chloride 2% (1 ml) (IM group). All patients were
blindfolded for the procedure. Evaluations were performed at baseline and 1, 4, 8 and 12 weeks post-intervention. The following
instruments were used: VAS for knee pain, as primary outcome, VAS for knee morning stiffness and edema; the ACR 20, 50 and 70%
improvement criteria; knee circumference and goniometry; Likert's scale of improvement; daily use of oral glucocorticoid and
NSAIDs, blood pressure and adverse effects. The researchers found that patients in the IAI group had significantly better results for
VAS for knee pain, edema and morning stiffness as well as for improvement evaluation after intervention according to the patient
(pb 0.001) and physician (p= 0.02). The results demonstrate that intraarticular injection with glucocorticoids is superior to its
systemic use for the management of monoarticular synovitis in rheumatoid patients. The intraarticular approach showed better
results in terms of local inflammatory variables and improvement evaluation by the patient and physician.