Atopy, autoimmunity, and the TH1/TH2 balance

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http://www.jpeds.com/article/PIIS0022347600675406/fulltext

The Journal of Pediatrics

October 2000 • Volume 137 • Number 4

Editorials

Atopy, autoimmunity, and the TH1/TH2 balance

Sampath Prahalad, MD [MEDLINE LOOKUP]

Abbreviations:

IDDM

Insulin-dependent diabetes

mellitus

IgE

Immunoglobulin E

IL

Interleukin

JRA

Juvenile rheumatoid arthritis

RA

Rheumatoid arthritis

The functional classification of murine CD4+ T helper cell

clones into distinct subtypes, designated T H1

and T H2 , based primarily on the pattern of

their cytokine production, has greatly enhanced our understanding of

T-cell biology.1 The existence of

TH1 and TH2 subsets has since been reported in

humans as well.2

See related article, p. 470 .

The concept of a type 1 or type 2 response has now been broadened to

include other cells such as cytotoxic (CD8+) T cells. These

two subsets of the T cells are characterized by differences in the

cytokines produced, transcription factors involved, the nature of the

immune responses mediated, and their disease

associations.3 TH1 cells

are characterized by the production of interleukin-2, interferon- , and

tumor necrosis factor- . In the absence of IL-4, IL-12, produced by

activated macrophages and dendritic cells, is the principal

TH1-inducing cytokine; its actions are mediated by the

transcription factor Stat4. TH1 cells are critical in the

defense against intracellular pathogens, eliciting phagocyte-mediated

responses. TH1-dominant responses are associated with

inflammation and injury and are exemplified by the delayed

hypersensitivity reaction. Thus TH1 cells are believed to play

a crucial role in cell-mediated immunity. Many autoimmune diseases

including rheumatoid arthritis, juvenile rheumatoid arthritis,

insulin-dependent diabetes mellitus, and multiple sclerosis are

associated with a TH1 phenotype. The signature cytokines of

the TH2 cells are IL-4 and IL-5, but TH2 cells also

produce IL-6 and IL-13. IL-10, although thought to be predominantly a

TH2 cytokine, can be secreted by TH1 cells as

well.3 IL-4 is the principal cytokine

that induces naive T-cell precursors to differentiate into TH2

cells, mediated by the transcription factor Stat6. IL-4 is involved in

B-cell switching to produce immunoglobulin E, and IL-5 is important for

eosinophil activation. TH2 cells play an important role in

humoral immunity. TH2 cells and their cytokines are associated

with atopic and allergic disorders. In addition, several cytokines

produced by TH2 cells such as IL-4, IL-10, and IL-13 have

anti-inflammatory actions.

It is now believed that the same T-cell precursor (designated

TH0 ), a mature, naive CD4+ T lymphocyte, is

capable of developing either a TH1 or TH2

phenotype.3 Once a T-cell immune

response begins to develop along one pathway, it tends to be

progressively polarized in that direction. Ouyang et

al4 showed that the transcription

factor GATA-3 directly repressed TH1 development, in an

IL-4–independent mechanism, which may involve repression of IL-12. This

suggests that the expression of GATA-3 and IL-12 signaling are mutually

antagonistic, facilitating dominance of one pathway over the other during

early development of the T helper cell. Besides cytokines, other factors

that determine the balance between TH1 and TH2

subsets in immune responses include the type of antigen-presenting cell,

the antigenic dose, and the strength of stimulation and

co-stimulation.

The TH1 and TH2 pathways each control a unique set

of immune responses, promoting the development of cells of the same

subset while suppressing the expansion and effector cells of the other

subset. Factors that alter this balance between these two subsets may

drive the immune response toward one pathway or the other. Although this

description is simplistic, the TH1/TH2 paradigm is

a useful one. As stated earlier, many autoimmune diseases are associated

with a TH1 phenotype, and allergic/atopic diseases are

associated with a TH2 phenotype. Given the polarization of the

developing T-cell response into one of these two types, it is reasonable

to speculate that autoimmune and allergic diseases represent two ends of

the same spectrum of immune responses and that these two types of

disorders would be mutually exclusive. In this issue of The Journal, the

EURODIAB Substudy 2 Study Group5

reports results that aimed to determine whether occurrence of atopic

diseases early in life is associated with a reduced risk of development

of type 1 IDDM. In a multicenter, population-based, case-control study,

the authors collected data on atopic diseases (asthma, eczema, and

allergic conjunctivitis) from children with type 1 IDDM and age-matched

control subjects. They found a decreased prevalence of atopic diseases,

in particular asthma, in children with IDDM. The risk reductions

associated with the atopic diseases were marked in children in the 10- to

14-year age group (odds ratio 0.59; 95% CI 0.42-0.83). A negative

association between atopy and IDDM has been previously described. In 1971

Hermansson et al6 reported a lower

frequency of atopy in children with IDDM, and their siblings as well,

compared with control subjects. Douek et

al7 found that a significantly lower

proportion of children with IDDM had symptoms of asthma, compared with

siblings or control subjects. The frequency and the severity of the

symptoms were also significantly lower among the children with IDDM.

However, the differences seen were for self-reported symptoms of asthma,

but not an actual diagnosis of asthma, which was similar in all 3

groups.

In addition to these epidemiologic studies, there is evidence from the

laboratory that supports the TH1/TH2 paradigm.

Rapoport et al8 investigated the

secretory patterns of interferon- , IL-2, IL-4, and IL-10 from stimulated

peripheral blood mononuclear cells from patients with IDDM and control

subjects. Patients with IDDM had an early decreased secretion of the

TH2 cytokines IL-4 and IL-10 and a late increased secretion of

the TH1 cytokines IL-2 and interferon- , providing evidence

for impairment of the TH1 and TH2 cytokine

secretory pattern in patients with IDDM.

Patients with RA, another TH1-mediated disease, have also been

investigated for the prevalence of TH2-mediated diseases.

Verhoef et al9 demonstrated that the

prevalence of hay fever in patients with RA was significantly lower than

that in patients without RA (4% vs 8%). Those patients with RA who had

hay fever had less severe disease compared with control patients with RA

(without hay fever) as determined by the erythrocyte sedimentation rate,

C-reactive protein level, joint score, and radiographic joint damage

score. Allanore et al10 reported that

the incidence and point prevalence of atopy was lower among patients with

RA than control subjects. These studies support the notion that

TH1 and TH2 diseases are mutually exclusive and

that the occurrence of a TH2-mediated disease, such as atopy,

might be protective against the development of a TH1-mediated

autoimmune disease.

However, not all studies support this view. Stromberg et

al,11 in a study of 81 children with

type 1 IDDM and 72 control subjects, did not find a significant

difference in prevalence of atopic disease as defined by history,

clinical features, skin prick test results, serum IgE, or circulating IgE

antibodies to allergens.11 Another

study showed that children with juvenile chronic arthritis, another

TH1-mediated disease, had no abnormalities of their responses

to inhalational allergens or IgE production compared with control

subjects.12 O’Driscoll et

al13 compared 40 patients with RA (9

of whom were receiving steroids) and 40 age- and sex-matched control

subjects and failed to detect a significant difference between the two

groups with respect to prevalence of positive skin prick test results,

atopic diseases, blood eosinophil counts, or total serum

IgE.13 Although these negative

studies are hospital-based and are limited by small sample sizes, they

emphasize the complexity of the interactions between various components

of the immune system. Measurement of cytokines from peripheral blood

cells or the serum may not be representative of the true nature of a

localized inflammatory response, with its particular cytokine and

cellular environment. In addition, cytokines are pleiotropic, being

produced by more than one type of cell and having many targets with

different effects. Thus attempts to dichotomize complex diseases in terms

of just TH1 or TH2 may be an oversimplification. In

fact, TH2 responses mediating IDDM have been reported, and

this disease could be mediated by both TH1 and TH2

cells.14 JRA provides another example

of the complexity of the TH1/TH2 balance. There is

evidence that JRA is a TH1-mediated

disease.15 Murray et

al16 demonstrated that synovial fluid

from patients with pauciarticular disease significantly overexpressed

IL-4 messenger RNA compared with synovial fluid from patients with

polyarticular JRA and RA. Thus it is of interest that the TH2

cytokine IL-4 is characteristic of pauciarticular JRA, which has a better

overall articular prognosis than polyarticular JRA.

Natural infection, mediated by IL-12, is believed to promote the

differentiation of T cells into a TH1 phenotype.

Immunizations, on the other hand, promote the development of a

TH2 phenotype.17 The

decreasing incidence of natural infections in the Westernized world

(hygiene hypothesis),18 in

combination with the increasing success of the immunization programs,

would be expected to tilt the balance toward TH2, depriving

the immune system of signals that promote TH1 development.

This raises the question of whether this tilt toward TH2 will

alter the prevalence of TH1-mediated

diseases.19 Interestingly, evidence

for such a trend has been presented by Spector et

al20 who reported that there was a

secular decline in the prevalence of RA and rheumatoid factor in

women.

In conclusion, establishing that TH1 and TH2

diseases are mutually antagonistic would lend further support for

attempts to promote one type of T-cell response selectively, in order to

alter or control the other and to preferentially manipulate the cytokine

network. This is part of the rationale behind trials of oral tolerance,

in which antigen is administered orally to preferentially inhibit

TH1 responses in the

periphery.21 The EURODIAB Substudy 2

Study Group5 has provided further

evidence in support of the TH1/TH2

paradigm.

Back to Article Outline

Acknowledgements I thank Gurjit K. Khurana Hershey,

MD, PhD, and N. Glass, MD, for critically reviewing the

manuscript.

Back to Article Outline

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doi:10.1067/mpd.2000.110300

© 2000 Mosby, Inc. All rights reserved.