Atopy, autoimmunity, and the TH1/TH2 balance

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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 TH1 and TH2, 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-4­independent 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.

I thank Gurjit K. Khurana Hershey, MD, PhD, and N. Glass, MD, for

critically reviewing the manuscript.

References

References

TOP

1. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two

types of murine helper T cell clone. I. Definition

according to profiles of lymphokine activities and secreted proteins.

J Immunol 1986;136:2348-57.

MEDLINE

2. Romagnani S. Human TH1 and TH2 subsets: doubt no more. Immunol

Today 1991;12:256-7.

MEDLINE

3. Abbas AK, KM, Sher A. Functional diversity of helper T

lymphocytes. Nature 1996;383:787-93.

MEDLINE

4. Ouyang W, Ranganath SH, Weindel K, Bhattacharya D, TL, Sha

WC, et al. Inhibition of Th1 development

mediated by GATA-3 through an IL-4-independent mechanism. Immunity

1998;9:745-55.

MEDLINE

5. The EURODIAB Substudy 2 Study Group. Decreased prevalence of

atopic diseases in children with diabetes. J Pediatr

2000; 137:470-4.

MEDLINE

ABSTRACT

FULL TEXT

6. Hermansson B, Holmgren G, son G. Juvenile diabetes mellitus

and atopy. Hum Hered 1971;21:504-8.

MEDLINE

7. Douek IF, Leech NJ, Gillmor HA, Bingley PJ, Gale EA. Children with

type-1 diabetes and their unaffected siblings have

fewer symptoms of asthma [letter]. Lancet 1999;353:1850.

MEDLINE

8. Rapoport MJ, Mor A, Vardi P, Ramot Y, Winker R, Hindi A, et al.

Decreased secretion of Th2 cytokines precedes

up-regulated and delayed secretion of Th1 cytokines in activated

peripheral blood mononuclear cells from patients with

insulin-dependent diabetes mellitus. J Autoimmun 1998;11:635-42.

MEDLINE

CROSSREF

9. Verhoef CM, van Roon JA, Vianen ME, Bruijnzeel-Koomen CA, Lafeber

FP, Bijlsma JW. Mutual antagonism of rheumatoid

arthritis and hay fever: a role for type 1/type 2 T cell balance. Ann

Rheum Dis 1998;57:275-80.

MEDLINE

10. Allanore Y, Hilliquin P, Coste J, Renoux M, Menkes CJ. Decreased

prevalence of atopy in rheumatoid arthritis [letter].

Lancet 1998;351:497.

MEDLINE

11. Stromberg LG, Ludvigsson GJ, Bjorksten B. Atopic allergy and

delayed hypersensitivity in children with diabetes. J

Allergy Clin Immunol 1995;96:188-92.

MEDLINE

ABSTRACT

FULL TEXT

12. Peskett SA, Platts-Mills TA, Ansell BM, Stearnes GN. Incidence of

atopy in rheumatic disease. J Rheumatol

1981;8:321-4.

MEDLINE

13. O’Driscoll BR, Milburn HJ, Kemeny DM, Cochrane GM, Panayi GS.

Atopy and rheumatoid arthritis. Clin Allergy

1985;15:547-53.

MEDLINE

14. Azar ST, Tamim H, Beyhum HN, Habbal MZ, Almawi WY. Type I

(insulin-dependent) diabetes is a Th1- and

Th2-mediated autoimmune disease. Clin Diagn Lab Immunol 1999;6:306-10.

MEDLINE

15. Wedderburn LR, Woo P. Type 1 and type 2 immune responses in

children: their relevance in juvenile arthritis. Springer

Semin Immunopathol 1999; 21:361-74.

MEDLINE

16. Murray KJ, Grom AA, SD, Lieuwen D, Passo MH, Glass DN.

Contrasting cytokine profiles in the synovium of

different forms of juvenile rheumatoid arthritis and juvenile

spondyloarthropathy: prominence of interleukin 4 in restricted

disease. J Rheumatol 1998;25:1388-98.

MEDLINE

17. Rook GA, Stanford JL. Give us this day our daily germs. Immunol

Today 1998;19:113-6.

MEDLINE

CROSSREF

18. Holgate ST. The epidemic of allergy and asthma. Nature

1999;402(Suppl):B2-4.

MEDLINE

19. Gaston JS. Will the increasing prevalence of atopy have a

favourable impact on rheumatoid arthritis? [editorial]. Ann

Rheum Dis 1998;57:265-7.

MEDLINE

20. Spector TD, Hart DJ, RJ. Prevalence of rheumatoid

arthritis and rheumatoid factor in women: evidence for a

secular decline. Ann Rheum Dis 1993;52:254-7.

MEDLINE

21. Weiner HL. Oral tolerance: immune mechanisms and treatment of

autoimmune diseases. Immunol Today 1997;

18:335-43.

MEDLINE

Publishing and Reprint Information

Publishing and Reprint Information

TOP

S. Rowe Division of Rheumatology, Children’s Hospital Medical

Center, Department of Pediatrics, University of

Cincinnati College of Medicine, Cincinnati, OH 45229-3039

J Pediatr 2000;137:446-9.

Copyright © 2000 by Mosby, Inc

0022-3476/2000/$12.00 + 0 9/18/110300

doi:10.1067/mpd.2000.110300

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