Clinical and Diagnostic Laboratory Immunology, May 1999, p. 306-310, Vol. 6, No. 3
1071-412X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
MINIREVIEW
Type I (Insulin-Dependent) Diabetes Is a Th1-
and Th2-Mediated Autoimmune Disease
Sami T.
Azar,1,2
Hala
Tamim,3
Hayfa N.
Beyhum,4
M. Zouhair
Habbal,5 and
Wassim Y.
Almawi6,*
Departments of Internal
Medicine,1
Biochemistry,4 and Clinical
Pathology & Laboratory Medicine,5 American
University of Beirut, Faculty of Health Sciences, Balamand
University,3 and Department of
Laboratory Medicine, St. George Hospital,6
Beirut, and Diabetes Unit, Chronic Care Center,
Hazmieh,2 Lebanon
 |
INTRODUCTION |
Type I (insulin-dependent) diabetes
(IDDM) is an autoimmune disease with an unknown etiology but with a
definite outcome, resulting in the progressive misdirected immunologic
destruction of insulin-secreting pancreatic 
islet cells by
autoreactive leukocytes and their mediators (3). Even
though the precise cause of the disease remains unclear, a combination
of genetic, immunologic, and nongenetic factors contributes to the
onset and progression of IDDM (3, 52). Specific HLA
antigens, in particular DR3 and DR4, have been associated with
increased risk for IDDM development (52, 89), while DR2
alleles generally have been described as "protective" of IDDM
(86). In addition to HLA predisposing factors, viral
infection (8), psychological factors (73), and
dietary factors (8), among others, have been described as
predisposing factors. Other investigators failed to demonstrate a
strong cause-and-effect link between these factors and IDDM, which
highlighted the need for further investigation and identification of
causative agents and mechanisms underlying the pathogenesis of IDDM
(77).
The frequent coexistence of IDDM with immune disorders is well
established and results from an inherent dysregulation in humoral immunity and cell-mediated immunity (3, 8). This is
exemplified by the presence of autoreactive antibodies targeting
select -cell constituents and other autoantigens (23,
28), circulating autoreactive T cells (78, 80),
heightened expression of adhesion molecules (37, 60),
reduced levels of serum cytokine inhibitors (57), and
sustained expression of cytokines and their high-affinity receptors
(36, 82). The development of hyperglycemia, a hallmark of IDDM, appears at later stages of the disease, months or years after
the initiation of targeted autoimmune destruction of cells (81).
The involvement of T-cell- and macrophage-derived cytokines in IDDM
pathogenesis remains the subject of intense investigation; conclusions
were largely based on studies with the genetically IDDM-predisposed
nonobese diabetic (NOD) mice and BioBreeding (BB) rats, animal models
which display many of the characteristics of human type I diabetes
(4), and have focused on direct cytotoxic and indirect
immunomodulatory effects of cytokines in mediating -cell destruction
(58, 82). Based on such studies, it was concluded that Th1
cytokines exacerbate, while Th2 cytokines protect from, IDDM (70,
72). However, contrary evidence is accumulating which
demonstrates that the progression of IDDM from insulitis (pancreatic
mononuclear cell infiltration) to frank hyperglycemia is under the
control of both Th1 and Th2 cells and their respective cytokines
(2, 46, 80, 93). This review focuses on the role of
cytokines in IDDM pathogenesis and attempts to reconcile and
accommodate the (apparently) conflicting reports pertaining to the
protective and damaging roles of Th1 and Th2 cytokines in the context
of autoimmune-mediated dysregulation of immunity. For discussion about
other facets of altered immunity in IDDM, we refer the reader to
excellent reviews published elsewhere (9, 11, 33).
| |
OVERVIEW OF T-CELL ACTIVATION |
Antigen-specific activation of naive CD4+ T cells
requires two signals. The first signal is imparted by interaction of
the multimeric T-cell receptor (TcR)-CD3 complex with processed antigen expressed in conjunction with major histocompatibility complex class II protein by antigen-presenting cells (APC). The second signal is provided by costimulatory molecules which complement TcR-CD3
signals in augmenting T-cell activation (26, 29). At least
three major signal transduction pathways operate as a consequence
of T-cell activation: (i) phospholipase C-
1 pathway, resulting in
the hydrolysis of phosphatidylinositol 4,5-bisphosphate (18)
and the generation of 1,4,5-inositol trisphosphate and diacylglycerol
(53, 69), (ii) p21ras/RAF kinase
pathway, also referred to as the "classical mitogen-activated protein
kinase pathway" (38), and (iii) the phosphatidylinositol 3'-OH kinase/GDP-Rac, referred to as the "alternative
MAPK-signaling pathway" (12). Depending on the
intensity of the signal generated, duration of stimulation, and the
contribution of costimulatory molecules, coupling to more than one
signal transduction pathway is possible, which determines the outcome
of the functional response (17, 42).
Engagement of the TcR in the absence of appropriate costimulation
results in a transient activation with very little interleukin-2 (IL-2)
production, followed by a sharp decline in activation
(19). The provision of secreted (49, 62) and
cell-bound (7, 51) costimulatory molecules, in synergy with
TcR-CD3 signals, significantly augments cytokine expression at
the transcriptional and posttranscriptional levels. This results in
stabilization of IL-2 and other cytokine mRNA transcripts (50,
51), abrogation of anergy (31), and enhancement of
cell viability as a result of inhibition of activation-induced cell
death, or apoptosis (71).
Insofar as costimulatory signals determine whether TcR recognition of
antigen will lead to activation or anergy, a role for altered
costimulation in the pathogenesis of autoimmune disorders, including
IDDM (see below) (41, 88), was proposed. This was supported
by the findings that (i) blockade of cell-bound costimulatory molecules
by chimeric toxin-immunoglobulin (Ig) fusion proteins induced
hyporesponsiveness (13, 48) and (ii) aberrant expression of
costimulatory signals may activate autoreactive T cells, thereby inducing and/or exacerbating autoimmunity (48). This has
revived interest in manipulating costimulatory pathways as new
strategies for controlling autoimmune diseases, including IDDM (9,
88).
| |
IMMUNOLOGY OF TH CELLS |
In 1986, Mosmann et al. reported that upon activation
CD4+ T cells will differentiate into two distinct T helper
(Th) cell clones expressing distinct cytokine profiles and effector
functions (64), thus giving rise to a unifying Th1/Th2
paradigm. Central to this are the specific requirements for induction
of Th1 and Th2 activities, including the nature of APC
(macrophages, dentritic cells, or B cells) (21, 54),
strength of TcR binding to processed antigen, and Th1 and Th2
cytokines (65, 74). Th1 cells produce IL-2 and gamma
interferon (IFN-), while Th2 cells produce IL-4, IL-5, IL-10, and
IL-13 (65, 73). Th0 cells, which produce both Th1 and Th2
cytokines, are generally regarded as precursors for Th1 and Th2 cells,
being swayed into differentiating into either pathway in response to
external stimuli (76) and also in response to Th1 and Th2
cytokines (55, 84). It should be noted that these two
polarized patterns of cytokine expression represent extremes of many
possible outcomes (40, 61).
Th1 and Th2 cells negatively cross-regulate the function of one another
through their respective cytokines (55, 74). Th1 cytokines
induce Th1 activity and block Th2 activity (34, 59), whereas Th2 cytokines promote Th2 activity while inhibiting
Th1 activity (83). This indicates that induction of one Th
program is accompanied by a corresponding decline in the activation of the other Th program (40). It remains to be seen whether
this results from a shifting from one Th subset to another or,
alternatively, from suppression of the growth of cells with
committed phenotypes (1, 40). In any event, difference in
cytokine secretion between Th1 and Th2 cells translates into
functional differences, as Th1 cells, by producing IFN-,
activate CD8+ T cells and macrophages and promote
cell-mediated immunity (1). Th2 cells stimulate IgM, IgG1,
and IgE synthesis by B cells and activate eosinophils, thus
promoting hypersensitivity reactions due to their capacity to produce
IL-4 and IL-5 (15, 74).
| |
PATHOPHYSIOLOGY OF CYTOKINES IN IDDM |
In view of their role in macrophage activation and induction of
delayed-type hypersensitivity reactions, Th1 cells were regarded as
proinflammatory, while Th2 cells, which inhibit Th1 activity (see
above), were considered anti-inflammatory (65, 84).
Consistent with this characterization were the findings that IL-4 and
IL-10
exclusive products of Th2 cellsinhibited IL-2-mediated
responses and suppressed the production of the (proinflammatory) Th1
cytokines (20, 85). Accordingly, it was speculated that Th1
cytokines play a direct role in the pathogenesis and progression of
IDDM, while Th2 cytokines should afford protection against Th1-mediated
destruction of islet cells. However, recent reports argued against
this oversimplification (61), as Th2 cells and their
mediators were shown to be involved in IDDM pathogenesis through
facilitation of pancreatic mononuclear-cell infiltration (32,
87) and acceleration of islet cell destruction (44,
68). This prompted the conclusion that IDDM is a Th1- and
Th2-mediated disease (see below).
| |
IDDM: A TH1-MEDIATED EVENT |
Evidence from human studies and animal models supports a direct
role for Th1 cells and their respective cytokines in the pathogenesis and progression of IDDM. This conclusion is based on the findings that
recent-onset IDDM was associated with an increase in the expression of Th1 cytokines and a corresponding decline in the production of Th2 (IL-4) cytokines (6, 35, 79). Destruction of cells was suggested to be due to a frank Th1-driven insulitis (22), and it was suggested that IDDM could be abrogated by
induction of Th2 cytokine expression (30) or by treatment
with the Th2 cytokines IL-4 and IL-10 (22, 72). The latter
were described to act through inhibition of the production of Th1
cytokines. Furthermore, the predominance of Th1 cytokines in -islet
cell infiltrates in female, but not male, NOD mice was described
as a major predisposing factor for developing anti--cell
immunity, and subsequently overt diabetes, in female, but not male, NOD mice littermates (25).
Mechanistically, Th1 cytokines induced and accelerated -cell
destruction through direct and indirect mechanisms. Th1 cytokines, including IFN-, exerted their effects primarily at the level of
macrophage and CD8+ T-cell activation, enhancing
infiltration of these cells into the islets, thus accelerating -cell
destruction through the release of preformed and de novo-synthesized
cytotoxic mediators (nitric oxide, oxygen radicals, serine esterases,
etc.) (24). In addition to these direct effects, and owing
to their capacity to suppress the production of Th2 cytokines, Th1
cytokines facilitated -cell destruction indirectly by several
mechanisms. These included induction of the activation and expansion of
bystander autoreactive T cells, which increased their overall
proportion (47), and suppression of the production of
soluble cytokine antagonists, including the IL-1 receptor antagonist
(22). The latter resulted in stimulation of IL-1 production
by macrophages (22) and, in conjunction with continued
autoantigenic stimulation, significant augmentation in the expression
of IL-2 and other Th1 cytokines. Insofar as IDDM is associated with
reduction in the production and activation of serum cytokine inhibitors
(57), and as Th1 cytokines potentiated the production and
effector functions of monokines (IL-1 and tumor necrosis factor alpha)
(56), this eventually amplified the cascade of -cell destruction.
| |
IDDM: A TH2-MEDIATED EVENT |
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
hypothesis were the findings that insulitis associated with new-onset
IDDM involved pancreatic homing of Th2 cells (39, 60) and
the predominance of Th2 cytokines (45, 60, 90). Pancreatic
expression of Th2 cytokines did not overcome autoimmune destruction of
the pancreas (46, 66) but rather accelerated it (5, 68,
93). In addition, induction of Th2-mediated antibody responses to
a -cell constituent led to a rapid spread of Th2 immunity to
unrelated -cell antigens and, in conjunction with Th1 cytokines, to
exacerbation of IDDM (87). In addition, peri-insulitis and
insulitis were prevented by treatment of NOD mice with anti-IL-10
antibodies (44). Furthermore, IDDM was not prevented by
adoptive transfer of Th2 cells (even at a 10-fold excess relative to
Th1 cells [39]) or by induction of Th2 activity by a
neutralizing anti-IL-12 monoclonal antibody (MAb) (91).
It was of interest that this "Th2-induced" component of
anti--cell immunity appeared to be mediated principally by IL-10 but not by IL-4, thus making it unclear whether this effect was a
generalized feature of Th2 cytokines or, alternatively, unique to
IL-10. In this regard, it was demonstrated that local production of
IL-10, but not IL-4, accelerated autoimmune destruction of islet
cells (46, 63, 68). In addition, NOD mice were protected from development of overt diabetes by a neutralizing anti-IL-10 MAb but
not anti-IL-4 MAbs, which were described to be ineffective in altering
the course of Th2 autoimmune destruction of pancreatic islet
cells (68). Furthermore, in contrast to IL-10
(68), tissue expression of IL-4 (67) led to
a nondestructive insulitis. These and other results underscore
the fact that the role of Th2 cytokines in IDDM pathogenesis is a
complex one and depends on the relative contribution of individual
cytokines in the process. This warrants further scrutiny in assigning a
generalized pathogenic role for Th2 cytokines (versus a specific effect
of IL-10) in the pathogenesis and progression of IDDM.
In any event, Th2 cytokines can no longer be viewed as
"protective" of IDDM, and their use as immunotherapy needs
reassessment in view of their direct role in promoting insulitis and
-cell destruction. Functionally, Th2 cytokines exert their effects
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, due to its role as a B-cell (27, 75)- and
cytotoxic-T-cell (14)-stimulatory or differentiating factor,
IL-10 may stimulate activated T cells and B cells. Differential
responsiveness of different APC types (macrophages, B cells, dendritic
cells) to antigenic stimulation (21) and to IL-10 action
(54) has been reported. Third, Th2 cytokines promote
peri-insulitis and frank insulitis by enhancing major
histocompatibility complex class II expression (63, 92) or
by altering the expression of endothelium-bound addressin, thereby
stimulating accumulation of macrophages, B cells, and eosinophils
(93). Fourth, by augmenting cytokine production by
endothelial cells and other cell types (10, 16), local production of Th2 cytokines amplifies the cascade of
anti--cell immunity through activation of resident immune
cells and by facilitating the pancreatic infiltration by other cell types.
| |
TH1- VERSUS TH2-DRIVEN INSULITIS |
It is evident that Th1 cells are not the sole mediators of
-islet cell destruction, that Th2 cells are not inhibitory or benign, as they are capable of inducing -islet destruction, and that
both Th1 and Th2 cytokines appear to cooperate in driving -islet
cell destruction, eventually leading to hyperglycemia. However,
the types of lesions differ between Th1- and Th2-driven insulitis (39, 68). Th1 lesions comprised focally
confined insulitis consisting primarily of CD8+ and
CD4+ T cells, and islet cells die by apoptosis, thereby
sparing surrounding exocrine tissue (43). On the other hand,
Th2 lesions are more dispersed and consist primarily of eosinophils,
macrophages, and fibroblasts, with a notable sparsity of T cells
(67), and islets die by necrosis. Also, there is the
accumulation of fibroblasts and the generation of the extensive
extracellular matrix and adipose tissue in Th2 lesions which
subsequently leads to tissue necrosis.
In addition to differences in lesion morphology, the kinetics of
-cell destruction differ between Th1- and Th2-driven
autoimmune attacks (45). Compared to a Th2-mounted
attack, Th1-driven injuries are more rapid and
aggressive and are sustained for a longer period, which suggests
that a Th2-mediated attack is responsible for the early phase of IDDM
(2) while Th1-driven responses are responsible for the
persistent and sustained attacks (44). It remains to be
determined whether the predominance of Th1 attacks in advanced IDDM
is a reflection of the expansion of Th1 clones and/or due to the
incapacity of Th2 clones to sustain an immunologic attack, as has been
suggested (87).
| |
CONCLUDING REMARKS |
The previous assignment of a pathogenic role to Th1 cells and a
protective role to Th2 cells and their respective cytokines in the
pathogenesis and progression of IDDM was largely based on artificial
conditions. This did not reflect the delicate balance and relative
contribution of each Th subset at distinct stages of the disease.
Accordingly, Th1 cells are not the sole instigators of IDDM, and Th2
cells are more harmful than previously believed.
A number of points are worth considering in this context. First, many
studies were based largely on in vitro observations using well-defined
experimental conditions which were not representative of the cytokine
milieu and/or the cellular network that are operative in the pancreas
during the autoimmune attack. Second, the Th1/Th2 cytokine-secreting
profile represents the extreme of many possible outcomes. Accordingly,
pushing the differentiation of one Th subset to the extreme by using
MAbs or recombinant cytokines is an exaggeration since this cannot be
duplicated in vivo. Third, assignment of a protective role to Th2
cytokines, including IL-10, was based on a well-documented effect
of IL-10. However, cytokines are pleiotropic; a cytokine may be
produced by more than one cell type and may exert its effect on several
target cells. Thus, assignment of a specific role to Th1 and Th2
cytokines cannot be fully addressed by 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. While it is
desirable and tempting to manipulate the Th1-Th2 balance in favor of a
benign or a protective immune response, future immunotherapy must take
into consideration the delicate balance between Th1 and Th2 cells
during distinct phases of IDDM.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Section of
Molecular Biology, Department of Laboratory Medicine, St.
George-Orthodox Hospital, P.O. Box 166378-6417, Beirut,
Lebanon. Phone: 961-3-812861. Fax: 961-1-582560.
| |
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Clinical and Diagnostic Laboratory Immunology, May 1999, p. 306-310, Vol. 6, No. 3
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Introduction
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