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Cytokine dysregulation in the hyperimmunoglobulinemia E syndrome

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Cytokine deficiencies, excesses, or imbalances are implicated in a number of

inflammatory and immunologic disorders such as Kawasaki disease, bronchial

asthma, rheumatoid arthritis, and several primary immunodeficiencies.

Cytokines, the low-molecular-weight hormones of the immune system, are many

in number (over 50 have been identified) diverse in their effects, and until

recently, difficult to assay. A few are available as therapeutic agents, for

example granulocyte colony-stimulating factor, granulocyte-macrophage

colony-stimulating factor, the interferons, and interleukin-2. Monoclonal

antibodies that interfere with their action, such as the anti-tumor necrosis

factor antibody infliximab and the anti-IL-2 receptor antibody daclizumab,

are also available for clinical use.

Like the endocrine hormones, cytokines act through specific cellular

receptors, so that abnormalities of receptor structure can result in

deficient binding and functional deficiency. Because cytokines are growth

and differentiating factors for multiple cells and tissues, abnormalities

can lead to protean manifestations involving many organ systems such as

those present in hyperimmunoglobulinemia E syndrome.

The hyper-IgE immunodeficiency syndrome is characterized by recurrent

staphylococcal infections of the lungs and skin and a markedly elevated

serum IgE level, usually exceeding 2000 IU/mL and sometimes as high as

20,000 IU/mL (normal, <100 IU/mL.)1 Most but not all patients have

characteristic facies and skeletal and connective tissue abnormalities

including osteoporosis. Many have neutrophil chemotactic defects,

particularly during infections.

Some patients lack a systemic or inflammatory response to the cutaneous

infections, leading to its colorful Old Testament eponym Job’s syndrome (“so

Satan went forth from the presence of the Lord, and afflicted Job with

loathsome sores from the sole of his foot to the crown of his head” Job

2:7).2

Other recent studies of hyper-IgE syndrome have defined the inheritance, the

phenotypic features, and dental abnormalities.3,4 Grimbacher et al4

confirmed that the inheritance pattern in familial cases best fits into an

autosomal dominant pattern with variable expression; 11 of their 30 patients

had affected relatives. Other family members had some but not all features

of the disease.

The characteristic facial features of coarse skin, prominent forehead,

deep-set eyes, prognathism, and thickened lower lip, nose, and ears were

recently quantitated.3,4 Grimbacher et al4 reported delayed shedding of

primary teeth, delayed eruption of permanent teeth, or both abnormalities in

72% of 30 patients. Because shedding and tooth development are independent,

this sometimes resulted in double rows of teeth. Of their patients, 57% had

bony fractures, 76% had scoliosis, and 68% had hypermobile joints.

Could these abnormalities be explained by cytokine dysregulation? Possibly,

because cytokines affect not only the immune system but also skeletal

maturation, collagen synthesis, and bone metabolism.

The article by Borges et al5 in this issue of The Journal shows a deficient

T-helper cell type I cytokine response in 10 of these patients. A type I

response is associated with production of IL-2, IL-12, IL-15, and

interferon-; promotes delayed hypersensitivity responses; and inhibits type

II cytokine responses. Type II responses, mediated by IL-4, IL-5, and IL-13,

promote antibody synthesis and activate antibody production, including IgE

production.6

Borges et al5 describe decreased in vitro IFN- production after specific

antigenic stimulation, particularly when the patients’ cells were activated

by staphylococcal antigens, the chief pathogen implicated in the disorder.

When the patients’ cells were pretreated with IL-12, a strong activator of

IFN- production, before antigen stimulation, the defect in IFN- was even

more striking. They postulate that deficient IFN- production may be

responsible for the elevated IgE levels and the variable defect in

neutrophil chemotaxis. Paganelli et al7 have also reported in vitro

deficiency of IFN- production; indeed, IFN- has been used therapeutically in

a few patients with hyper-IgE syndrome with suggestive clinical benefit.8

These reported observations must be tempered by the fact that the in vitro

defects, although statistically significant, were not striking or correlated

with clinical severity or levels of IgE. Further, Vercelli et al9 found that

IgE synthesis by B lymphocytes of patients with hyper-IgE syndrome was

relatively insensitive to suppression by IL-4 or IFN-. Garraud et al,10

however, were able to suppress IgE synthesis with a monoclonal antibody to

the IL-4 receptor in these patients.

Profound disruption of type I cytokine responses has recently been

identified in several patients with IFN- receptor, IL-12 receptor, or IL-12

mutations; these patients have severe and often fatal mycobacterial, but not

staphylococcal, infections.11 Further, most patients with hyper-IgE syndrome

have intact T-cell–mediated immunity and do not have mycobacterial

infections.

Despite these caveats, the cytokine defects observed in hyper-IgE syndrome

may provide a clue both to its pathogenesis and rational treatment. Further

therapeutic studies with IFN- and other regulatory cytokines are indicated.

REFERENCES

1. Buckley RH. Disorders of the IgE system. In: Stiehm ER, editor.

Immunologic disorders in infants and Children. 4th ed. Philadelphia: WB

Saunders Co; 1996. p. 409-22.

2. SD, Schaller J, Wedgwood RJ. Job’s syndrome. Lancet 1966;1:

1013-5. [MEDLINE]

3. Borges WG, Hensley T, Carey JC, Petrak BA, Hill HR. The face of Job. J

Pediatr 1998;133:303-5. [MEDLINE]

4. Grimbacher B, Holland SM, Gallin JI, Greenberg F, Hill SC, Malech HL, et

al. Hyper-IgE syndrome with recurrent infections—an autosomal dominant

multisystem disorder. N Engl J Med 1999;340:692-702. [MEDLINE]

5. Borges WG, Augustine NH, Hill HR. Defective interleukin-12/interferon-

pathway in patients with hyperimmunoglobulinemia E syndrome. J Pediatr

2000;136:176-80. [MEDLINE]

6. CB, Penix L, Melvin A, DB. Lymphokine regulation and the

role of abnormal regulation in immunodeficiency. Clin Immunol Immunopathol

1993;67:S25-32. [MEDLINE]

7. Paganelli R, Scala E, Capobianchi MR, Fanales-Belasio E, D’Offizi G,

Fiorilli M, et al. Selective deficiency of interferon-gamma production in

the hyper-IgE syndrome. Relationship to in vitro IgE synthesis. Clin Exp

Immunol 1991;84:28-33. [MEDLINE]

8. Petrak BA, Augustine HN, Hill HR. Recombinant human interferon gamma

treatment of patients with Job’s syndrome of hyperimmunoglobulinemia and

recurrent infections [abstract]. Clin Res 1994;4:1A.

9. Vercelli D, Jabara HH, Cunningham-Rundles C, Abrams JS, DB, Meyer

J, et al. Regulation of immunoglobulin (Ig)E synthesis in the hyper-IgE

syndrome. J Clin Invest 1990;85:1666-71. [MEDLINE]

10. Garraud O, Mollis SN, Holland SM, Sneller MC, Malech HL, Gallin JI, et

al. Regulation of immunoglobulin production in hyper-IgE (Job’s) syndrome. J

Allergy Clin Immunol 1999; 103:333-40. [MEDLINE]

11. Altare F, Jouanguy E, Lamhamedi S, Doffinger R, Fischer A, Casanova JL.

Mendelian susceptibility to mycobacterial infection in man. Curr Opin

Immunol 1998;10:413-7. [MEDLINE]

Publishing and Reprint Information TOP

Professor of Pediatrics, Chief, Division of Immunology/Allergy/Rheumatology,

UCLA Children’s Hospital, Los Angeles, CA 90095

J Pediatr 2000;136:141-3.

Copyright © 2000 by Mosby, Inc.

0022-3476/2000/$12.00 + 0 9/18/104389

doi:10.1067/mpd.2000.104389