The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 5 1497-1502
Copyright © 1999 by The Endocrine Society
T Helper Type 1 and 2 Cytokines Mediate the Onset and Progression of Type I (Insulin-Dependent) Diabetes
Wassim Y. Almawi,
Hala Tamim and
Sami T. Azar
Department of Laboratory Medicine, St. George Hospital
(W.Y.A.); the Faculty of Health Sciences, Balamand University
(H.T.); the Department of Internal Medicine, American University
of Beirut (S.T.A.), Beirut; and the Diabetes Unit, Chronic Care
Center (S.T.A.), Hazmieh, Lebanon
Address all correspondence and requests for reprints to: Dr. Wassim Y. Almawi, Molecular Biology Section, Department of Laboratory Medicine, St. George-Orthodox Hospital, P.O. Box 166378–6417, Beirut, Lebanon.
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Abstract
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Type I (insulin-dependent) diabetes mellitus (IDDM) is an autoimmune
disease that results from the destruction of insulin-secreting
pancreatic islet ß-cells by autoreactive cells and their mediators.
Although its exact cause is not completely understood, it is well
established that IDDM is associated with dysregulated humoral and
cellular immunity, exemplified by altered production of and response to
macrophage- and T cell-derived cytokines and a shift in T helper (Th)
cell differentiation in favor of a pathogenic Th1 pathway. Th1
cytokines, including interleukin-2 and interferon-
, induced islet
ß-cell destruction directly by accelerating activation-induced cell
death (apoptosis) and by up-regulating the expression of select
adhesion molecules, Th1 cytokines facilitated the pancreatic homing of
autoreactive leukocytes, hence enhancing ß-cell destruction. More
recently, a role for Th2 cytokines in IDDM pathogenesis was described.
Accordingly, local production of Th2 cytokines, in particular
interleukin-10, accelerated ß-cell destruction by enhancing
autoreactive cell infiltration of the pancreas (insulitis) through
modulation of the release of other cytokines and by modulating the
microvasculature. Whereas both Th1 and Th2 cytokines are present in
peripheral T cells and in the pancreas in IDDM, the mechanism of action
and the kinetics of a cell damage induced by Th1 and Th2 cytokines
appeared to be distinct. Collectively, this supports the idea that IDDM
is not an exclusive Th1-mediated disorder as was suggested, and that
both Th1 and Th2 cells and their respective mediators participate and
cooperate in inducing and sustaining pancreatic islet ß-cell
destruction in IDDM.
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Introduction
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TYPE I (insulin-dependent) diabetes (IDDM)
is an autoimmune disease characterized by insulin insufficiency that
results from a progressive immunological destruction of
insulin-secreting pancreatic islet ß-cells by autoreactive leukocytes
and their mediators (1). Although the exact nature of the inducing
agent(s) and the sequence of events leading to the autoimmune
destruction of islet ß-cells and subsequently hyperglycemia are
currently not completely understood, it is well established that
genetic, nongenetic, and immunological factors contribute to the
pathogenesis of IDDM (1, 2, 3). Specific human leukocyte antigen alleles,
in particular DR3 and DR4, were associated with an increased risk of
IDDM development (2, 4). Other human leukocyte antigens, such as DR2,
were described as protective of IDDM development (5). In addition to
genetic factors, nongenetic factors were shown to predispose for and
accelerate the development of overt diabetes in IDDM-prone individuals.
These included viral infection (6), psychological factors (7), and
dietary factors (such as cow milk) (6) among others. Other reports
could not confirm a strong cause and effect link between these factors
and IDDM, thereby highlighting the need for further investigation into
identifying the causative agent(s) and the mechanisms underlying the
onset and progression of IDDM (8).
IDDM is associated with altered humoral and cellular immunity (1, 6).
This was evidenced by the presence of autoreactive antibodies targeting
select ß-cell constituents and other autoantigens (9, 10),
circulating autoreactive T cells (11, 12), and heightened expression of
adhesion molecules (13, 14). In particular, IDDM was associated with
altered regulation of cytokine expression manifested in part by reduced
levels of serum cytokine inhibitors (15) coupled with sustained
expression of proinflammatory and immunoregulatory cytokines and their
high affinity receptors (16, 17, 18). The development of hyperglycemia, a
hallmark of IDDM, appears later in the course of the disease,
frequently following months or years of the initiation of the T
cell-targeted autoimmune destruction of islet ß-cells (19, 20).
The exact roles T cell- and macrophage-derived cytokines play in the
pathogenesis of IDDM remain the subject of intense investigation (20, 21). Conclusions reached were largely based on studies on the
genetically IDDM-predisposed animals, the nonobese diabetic (NOD) mice
and BioBreeding (BB) rats, both of which display many of the
characteristics of human IDDM (22). Based on these and other studies,
cytokines were shown to induce and/or exacerbate IDDM through direct
and indirect mechanisms. The former was through direct cytotoxicity,
whereas the latter included modulation of the activation, homing, and
effector (cytotoxic) functions of proinflammatory cells (17, 18, 23).
Although it is accepted that IDDM resulted from altered balance between
T helper type 1 and 2 (Th1 and Th2) cells, the exact roles Th1 and Th2
cells play in IDDM pathogenesis remain to be established. It was
suggested that Th1 cytokines promote whereas Th2 cytokines protect from
the onset and progression of IDDM (24, 25, 26). However, in some cases Th2
cells and their cytokines accelerated ß-cell destruction, hence
arguing against this exclusive and oversimplistic conclusion. It
appears that the onset and progression of IDDM from insulitis
(pancreatic mononuclear cell infiltration) to overt diabetes are
controlled by Th1 and Th2 cells together with their cytokines and other
mediators (12, 27, 28, 29). This review will focus on the roles Th1 and Th2
cytokines play in the pathogenesis of IDDM; for discussion about other
aspects of altered immunity in IDDM, the reader is referred to reviews
published previously (30, 31, 32).
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Biology of Th1 and Th2 cells
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Antigen-specific T cell activation requires two signals. One is
imparted by interaction of the T cell receptor (TcR)/CD3 complex with
the antigen:major histocompatibility complex class II protein complex
expressed by antigen-presenting cells (APC). The second signal is
provided by cell-bound and secreted costimulatory molecules which,
while not imparting any antigenic specificity, synergize with TcR/CD3
signals in augmenting T cell activation (33, 34). Several signal
transduction pathways operate as a result of T cell activation. These
include phospholipase C-1 pathway,
p21ras/RAF kinase (the classical
mitogen-activated protein kinase) pathway (35), and the
phosphatidylinositol 3'-hydroxykinase/GDP-Rac (the alternative
mitogen-activated protein kinase) signaling pathway (36). Coupling to
more than one signaling pathway is possible depending on the intensity
of the signal generated, the duration of stimulation, and the
contribution of costimulatory molecules, which, in turn, affects the
duration and outcome of the functional response (37, 38).
Secreted (39, 40) and cell-bound (41, 42) costimulatory molecules
synergized with TcR/CD3 signals in augmenting cytokine expression at
the transcriptional and posttranscriptional levels. This resulted in
stabilization of interleukin-2 (IL-2) and other cytokine messenger
ribonucleic acid transcripts (42, 43), abrogation of anergy (44), and
enhancement of cell viability largely as a result of antagonism of
activation-induced cell death/apoptotic signals (45). Insofar as
costimulatory signals determine whether TcR recognition of antigen will
lead to activation or to clonal anergy, a role for altered
costimulation in the pathogenesis of autoimmune diseases such as IDDM
(see below) (46, 47) was proposed. For example, blockade of cell-bound
costimulatory molecules by chimeric toxin/Ig fusion proteins induced
hyporesponsiveness (48, 49). In addition, it was suggested that
aberrant expression of costimulatory signals (in particular
CD28/CTLA-4) by activated autoreactive T cells may induce and/or
exacerbate autoimmunity (49). Accordingly, manipulating costimulatory
pathways was proposed as a potential strategy for managing autoimmune
diseases, including IDDM (32, 47).
Antigen-specific T cell activation results in the differentiation of
naive CD4+ Th cells into Th1 and Th2 clones based on their
pattern of cytokine production and effector functions. Th1 produce
IL-2, interferon- (IFN-), and tumor necrosis factor-
and
promote cell-mediated responses and delayed-type hypersensitivity
reactions (50, 51). Th2 cells produce IL-4, IL-5, IL-10, and IL-13 and
stimulate humoral immunity (50, 51). Th0 cells, which produce both Th1
and Th2 cytokines, represent either a distinct Th subset or a common
precursor for Th1 and Th2 cells that differentiates into either Th
subset in response to external stimuli (52) and to Th1 and Th2
cytokines (53, 54).
Several factors influence the development of Th1 and Th2 cells,
including the APC type (macrophages, dendritic cells, or B cells)
(55, 56, 57), the avidity of TcR interaction with antigen, and Th1/Th2
cytokines (50, 51, 58). Th1 and Th2 cells reciprocally regulate the
function of one another through their respective cytokines (51, 54).
Th1 cytokines, in particular IFN-, induce the development of Th1
cells and block the differentiation of Th2 cells and Th2-driven
responses (59, 60). In contrast, Th2 cytokines promote the
differentiation of Th2 cells while inhibiting Th1 activation and
Th1-induced responses (61), indicating that induction of one Th program
is accompanied by a corresponding decline in the activation of the
other Th program (62, 63). It remains to be seen whether this is the
result of a frank shifting to a specific Th subset or is due to
suppression of the growth of cells with committed phenotypes (62, 64).
It should be noted that these two polarized patterns of cytokine
expression represent extremes of many possible outcomes (62, 65).
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Pathophysiology of Th1 and Th2 cells in IDDM
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Understanding of the roles that Th1 and Th2 cells play in the
pathogenesis of IDDM was based on adoptive transfer experiments
demonstrating the capacity of Th1 cells to transfer diabetes to NOD
mouse recipients (66, 67, 68). Th2 cells generally protected from the
development of IDDM in NOD recipients, the latter acting presumably by
inhibiting local Th1 cell activity. Oral administration of insulin, in
particular the immunodominant B chain (68, 69, 70), was associated with
progressive reduction in ß-cell destruction in NOD mice and BB rats
concomitant with decreased expression of Th1 cytokines (71, 72, 73) and a
corresponding increase in Th2 cytokine expression (67, 73, 74). This
was due to the induction of an insulin-reactive Th clone that protected
recipient NOD mice from the development of IDDM in a cotransfer
experiment (67). Interestingly, both Th1 (70) and Th2 (67, 73)
insulin-reactive IDDM-protective Th cells were described. The latter
inducing a Th2 cytokine-secreting profile in recipient animals, and the
former allegedly acted by stimulation of transforming growth factor-ß
activity (70), which, in turn, altered a pathogenic Th1 to a protective
Th2 phenotype (55).
However, the generality of this conclusion remains to be seen in light
of reports documenting the failure of Th2 cells to alter the
progression of IDDM (66), but in some cases to precipitate overt
diabetes (29). Evidence implicating both Th1 and Th2 cells, in
particular their respective cytokines, in mediating ß-cell
destruction is a reflection of the dual role of Th1 and Th2 cytokines
in IDDM pathogenesis, depending on the cytokine and time after disease
onset (21). For example, IDDM was shown to be prevented by induction of
Th2 cells (75) or by treatment with the Th2 cytokines, IL-4 and IL-10,
which, in turn, blocked the production of Th1 cytokines (24, 76). In
addition, IL-10 (a Th2 cytokine) reportedly exacerbated IDDM by
facilitating pancreatic mononuclear cell infiltration (69, 77) and also
by accelerating islet ß-cell destruction by necrosis (78, 79). This
prompted the conclusion that IDDM is a Th1- and Th2-mediated autoimmune
disease (see below).
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IDDM: a Th1-mediated event
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Evidence from human and experimental animal studies supported a
direct role for Th1 cells and their cytokines in the onset and
progression of IDDM. These included the findings that recent-onset IDDM
was associated with the predominance of Th1 cytokines concomitant with
a corresponding decline in the production of Th2 (IL-4) cytokines
(80, 81, 82, 83). Destruction of ß-cells resulted from a frank Th1-driven
insulitis (76, 83), as revealed by the capacity of adoptively
transferred diabetogenic Th1 cells to provoke insulitis in NOD/SCID
mice (68). In addition, IDDM was abrogated by the induction of Th2
cytokine expression (75) or by treatment with the Th2 cytokines, IL-4
and IL-10 (24, 76), the latter acting through inhibition of production
of Th1 cytokines. Furthermore, the predominance of Th1 cytokines in
islet ß-cell infiltrates in female, but not male, NOD mice was
described as a major predisposing factor for developing anti-ß-cell
immunity, and subsequently overt diabetes, in female, but not male, NOD
littermates (84).
Th1 cytokines induced and aggravated ß-cell destruction through
direct and indirect mechanisms. Th1 cytokines, including IL-2 and
IFN-, acted primarily at the level of macrophage and
CD8+ T cell activation, enhancing infiltration of these
cells into the islets. Infiltrating cells induced and/or accelerated
ß-cell destruction largely by releasing preformed and newly
synthesized cytotoxic mediators (nitric oxide, oxygen radicals, serine
esterases, etc.) (85). Th1 cytokines also facilitated
ß-cell destruction indirectly by several mechanisms as a result of
their capacity to inhibit the production of Th2 cytokines and Th2 cell
activity. Th1 cytokines induced the activation and expansion of
bystander autoeactive T cells, resulting in an increase in their
overall proportions (86). Th1 cytokines also inhibited the production
of soluble cytokine antagonists, including the IL-1 receptor antagonist
(76), which resulted in stimulation of IL-1 production by macrophages
(76) and, coupled with sustained autoantigenic stimulation, resulted in
a significant augmentation in the expression of IL-2 and other Th1
cytokines. Insofar as IDDM is associated with reduction of the
production and activation of serum cytokine inhibitors (15), and as Th1
cytokines potentiated the production and effector functions of
monokines (IL-1 and tumor necrosis factor-) (87), this eventually
amplified the cascade of anti-ß-cell immunity.
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IDDM: a Th2-mediated event
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Whereas the role of Th1 cytokines in IDDM pathogenesis is well
established, a role for Th2 cytokines in precipitating certain aspects
of IDDM in the NOD mouse was recently proposed. Central to this role
were the findings that 1) insulitis associated with new-onset IDDM
involved pancreatic homing of Th2 cells (14, 66) and the predominance
of Th2 cytokines (14, 88, 89). Pancreatic expression of Th2 cytokines
did not overcome autoimmune destruction of the pancreas (28, 90), but,
rather, accelerated it (27, 79, 91). In addition, induction of
Th2-mediated antibody responses to a ß-cell constituent led to a
rapid spreading of Th2 immunity to unrelated ß-cell antigens and, in
association with Th1 cytokines, to exacerbation of IDDM (69).
Furthermore, whereas IDDM was not prevented by adoptive transfer of Th2
cells (even if present in a 10-fold excess of Th1 cells) (66) or by
induction of Th2 activity by neutralizing anti-IL-12 monoclonal
antibodies (92), periinsulitis and insulitis were prevented by
treatment of NOD mice with anti-IL-10 antibodies (78).
It was of interest to note that this Th2-induced component of
anti-ß-cell immunity was mediated principally by IL-10, but not by
IL-4, thus questioning whether this effect was a generalized feature of
Th2 cytokines or, alternatively, unique to IL-10. In this regard, it
was shown that local production of IL-10, but not IL-4, accelerated
autoimmune destruction of ß-islets (28, 79, 93). NOD mice were
protected from the development of overt diabetes by neutralizing
anti-IL-10 mb, but not anti-IL-4, monoclonal antibodies, which were
ineffective in altering the course of Th2 autoimmune destruction of
pancreatic islet ß-cells (79). Furthermore, in contrast to IL-10
(79), tissue expression of IL-4 (94) led to nondestructive insulitis.
This underscore the fact that the role Th2 cytokines play in the
pathogenesis of IDDM is complex and depends on the relative
contributions of individual cytokines in the process. This warrants
further scrutiny in assigning a generalized pathogenic role for Th2
cytokines (vs. a specific effect of IL-10) in the
pathogenesis and progression of IDDM.
Th2 cytokines can no longer be viewed as protective of IDDM, and their
claimed use as immunotherapy needs reassessing in view of their direct
role in promoting insulitis and ß-cell destruction. Functionally, Th2
cytokines exerted their affects through direct and indirect mechanisms.
First, Th2 cytokines, in particular IL-10, may promote necrosis through
occlusion of the microvasculature, thereby reducing the viability of
the larger islets. Second, IL-10 may exert immunostimulatory effects on
activated T and B cells due to its role as a stimulatory and
differentiation factor for B cells (95, 96) and cytotoxic T cells (97),
respectively, coupled with the differential responsiveness of different
APC types (macrophages, B cells, and dendritic cells) to antigenic
stimulation (57) and to IL-10 action (56). Third, Th2 cytokines promote
periinsulitis and frank insulitis by enhancing major histocompatibility
complex class II expression (93, 98) or by altering the expression of
endothelium-bound addressin, thereby stimulating the accumulation of
macrophages, B cells, and eosinophils (27). Fourth, by augmenting
cytokine production by endothelial cells and other cell types (99, 100), local production of Th2 cytokines amplified the cascade of
anti-ß-cell immunity through activation of resident immune cells and
by facilitating the pancreatic infiltration of other cell types.
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Functional considerations
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It is evident that Th1 cells are not the sole mediators of islet
ß-cell destruction, and that Th2 cells are not inhibitory or benign
as was previously suggested, as they are capable of inducing islet
ß-cell destruction. Th1 and Th2 cytokines appear to cooperate in
driving islet ß-cell destruction, eventually leading to
hyperglycemia. Functionally, the lesion morphology differs between Th1-
and Th2-driven insulitis (66, 79). Th1 lesions comprised focally
confined insulitis consisting primarily of CD8+ and
CD4+ T cells, and islet ß-cells die by apoptosis, thereby
sparing surrounding exocrine tissue (101). In contrast, Th2 lesions are
more dispersed and consisted primarily of esinophils, macrophages, and
fibroblasts, with a notable scarcity of T cells (90), and islet
ß-cells die by necrosis. In addition, there is the accumulation of
fibroblasts and the generation of extensive extracellular matrix and
adipose tissue in Th2 lesions that subsequently promoted tissue
necrosis.
In addition to morphological differences in lesions, the kinetics of
ß-cell destruction differ between Th1- and Th2-driven autoimmune
attacks (89). Compared to Th2-mounted attacks, Th1-driven attacks are
more rapid and aggressive and are sustained for a longer time period.
This suggested that Th2-mediated attacks are responsible for the early
phase of IDDM (29), whereas Th1-driven responses are responsible for
the persistent and sustained attacks (78). It remains to be seen
whether the predominance of Th1 attacks seen in advanced IDDM is a
reflection of the expansion of Th1 clones and/or is due to the
incapacity of Th2 clones to sustain an immunological attack, as
previously suggested (69).
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Concluding remarks
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The assignment of a pathogenic role for Th1 cells and a protective
role for Th2 cells and their respective cytokines in the onset and
progression of IDDM was largely based on artificial conditions that did
not reflect the delicate balance and relative contribution of each Th
subset throughout the disease. Accordingly, Th1 cells can no longer be
the sole instigators of IDDM, and Th2 cells appear to be more harmful
than previously believed. A number of points are worth considering in
this context. First, many studies were largely based on in
vitro observations using well defined experimental conditions that
were not representative of the cytokine milieu or the cellular network
that operates in the pancreas during the autoimmune attack. Second, the
designation of Th1 and Th2 cytokine-secreting profiles represents the
extreme of many possible outcomes. Accordingly, pushing the
differentiation of one Th subset to the extreme using monoclonal
antibodies or recombinant cytokines in vitro cannot be
duplicated in vivo (102, 103). Third, assignment of a
protective role for Th2 cytokines, including IL-10, was based on a well
documented effect of IL-10. However, cytokines such as IL-10 are
pleiotropic; a given cytokine may be produced by more than one cell
type and may exert its effect on several target cells (96, 97, 99, 104). Thus, the assignment of a specific role for Th1 and Th2 cytokines
cannot be addressed fully using these isolated conditions.
In conclusion, the onset and progression of IDDM are under the control
of both Th1 and Th2 cells and their respective cytokines. Although it
is desirable and tempting to manipulate Th1-Th2 balance in favor of a
benign or a protective immune response, future immunotherapies must
take into consideration the delicate balance between Th1 and Th2 cells
during distinct phases of IDDM.
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Acknowledgments
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The authors thank Dr. Soulaima Chamat for her helpful
suggestions. The excellent secretarial assistance of Ms. Saydeh Saliba
is greatly acknowledged.
Received September 23, 1998.
Revised February 1, 1999.
Accepted February 12, 1999.
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Top
Abstract
Introduction
