Children exhibit early signs of inflammation

Early-onset pediatric patients with moderate-to-severe atopic dermatitis show specific systemic signs of inflammation within months of onset and before chronic disease develops, shows research published in the Journal of the American Academy of Dermatology.

While there is growing evidence that adults with longstanding atopic dermatitis (AD) have systemic inflammation, with increases in multiple circulating inflammatory mediators, including cardiovascular risk proteins, and increased frequencies of activated blood T-cells, little is known about systemic inflammation in early pediatric atopic dermatitis.

Researchers assessed levels of inflammatory and cardiovascular risk proteins in the blood of 30 children under five who had been diagnosed with moderate-to-severe atopic dermatitis within the previous six months. They compared these levels with those of children of the same age without atopic dermatitis and those of adults with the condition.

Young, recently diagnosed children showed increased levels of Th2 (CCL13, CCL22) and Th17 (PI3/elafin), and increased levels of markers of tissue remodelling (MMP3/9/10, uPAR), endothelial activation (E-Selectin), T-cell activation (IL2RA), neutrophil activation (myeloperoxidase), lipid metabolism (FABP4), and growth factors (FGF21, TGF-alpha).
Total numbers of upregulated proteins were smaller (n=22) in these children with atopic dermatitis compared with adult with long-standing atopic dermatitis (n=61).

Only three proteins (CCL13, MMP10, TGF-α) were upregulated in the blood of both children and adults with atopic dermatitis. Adult blood included a broader array of Th2 (CCL17, CCL13, IL-13) and Th17 (CCL20) associated markers, and Th1 (CXCL9, CXCL10, CXCL11, IFN-γ) markers which were not upregulated in children’s blood, which is consistent with Th1 activation as a marker of chronicity.

Two markers which have been found to be raised in previous studies of pediatric atopic dermatitis - blood fractalkine (CX3CL1),  which is involved in T-cell retention in inflamed tissue and leukocyte adhesion to endothelial cells and is significantly increased in adult atopic dermatitis, and CCL17   - were not found to be raised in this study. The researchers point out that the children they studied were much younger and had less chronicity of disease than those in previous studies.

Clinical severity of atopic dermatitis was found to directly correspond with increased receptors for IL-33 and IL-36, but were inversely correlated with some Th1 markers (IFN-γ, CXCL11).

“Within months of pediatric atopic onset, systemic immune activation is present, withTh2/Th17 skewing but otherwise different proteomic patterns from adult atopic dermatitis,” says Amy Paller, M.D., department of dermatology at Northwestern University Feinberg School of Medicine, Chicago.

“Our data emphasize the systemic alterations within months of disease onset, potentially suggesting the need for more aggressive intervention before the establishment and perpetuation of chronic disease,” she adds, and to prevent so called “atopic march” where other atopic comorbidities develop. Atopic dermatitis is often associated with allergic comorbidities such as asthma, rhinoconjunctivitis, and food intolerances, and increasing evidence suggests that the condition may lead to increased risk of cardiovascular disease.

“Whole skin profiling studies of infants and young children with recent-onset atopic dermatitis have revealed considerable differences from adults with longstanding disease.  This study extends these differences to blood using a large-scale proteomic platform,” Dr. Paller says. “Future correlation of proteomic patterns with disease course, comorbidity development, and drug response may yield predictive biomarkers.”

There was a strong correlations between soluble blood ST2 levels and atopic dermatitis severity in the children. ST2 (IL1RL1) is the receptor for the Th2-inducing cytokine IL-33, and highly expressed on Th2 cells, mast cells and ILC2 cell mediating IL-33-mediated food and dust mite allergy via skin sensitization in mouse models.2, , ,7  but its role in humans is less clear.

Despite the fact that our pediatric patients did not yet suffer from allergic comorbidities, the observed correlation of ST2 expression with early disease severity, which has not been observed in older children and adults with  atopic dermatitis, suggests the need for investigation of the IL-33/ST2 axis in longitudinal studies beginning early after atopic dermatitis onset, Paller says. "These data might suggest that IL-33-targeting strategies,  which are being tested in adults could benefit some children with early AD.”

Blood IL1RL2, the receptor for IL-36 cytokines, was also positively correlated with skin disease.IL-36 cytokines are up-regulated in infant atopic dermatitis but, much less so, in adult disease so might be a biomarker specific for early disease, Paller suggests. “Anti-IL-36 treatment approaches, which are being tested for pustular psoriasis may also be applicable for children with atopic dermatitis.”

Low IFN-γ responses are believed to be a risk factor for developing atopic dermatitis and an inverse relationship was seen between severity of disease and Th1 markers (IFN-γ, CXCL11, and CCL2). An inverse relationship was also seen with other markers including mediators of neutrophil chemotaxis (CXCL5, CXCL6).
Dr. Paller speculates that these molecules could have a protective role, but adds “Future studies will be needed to confirm this hypothesis.”

References:

1 Brunner PM, He H, Pavel AB, et al. The blood proteomic signature of early-onset pediatric atopic dermatitis shows systemic inflammation and is distinct from adult long-standing disease. J Am Acad Dermatol. 2019;81(2):510-519.
2 Chong S, Lan H, Zeng K, Zhao X. Serum Fractalkine (CX3CL1) Concentration Correlates with Clinical Severity in Pediatric Atopic Dermatitis Patients. Ann Clin Lab Sci. 2016;46(2):168-73.
3 Thijs J, Krastev T, Weidinger S, et al. Biomarkers for atopic dermatitis: a systematic review and meta-analysis. Curr Opin Allergy Clin Immunol. 2015;15(5):453-60.
4 Brunner PM, Israel A, Zhang N, et al. Early-onset pediatric atopic dermatitis is characterized by T2/T17/T22-centered inflammation and lipid alterations. J Allergy Clin Immunol. 2018;141(6):2094-2106.
5 Zoltowska AM, Lei Y, Fuchs B, Rask C, Adner M, Nilsson GP. The interleukin-33 receptor ST2 is important for the development of peripheral airway hyperresponsiveness and inflammation in a house dust mite mouse model of asthma. Clin Exp Allergy. 2016;46(3):479-90.
6 Galand C, Leyva-castillo JM, Yoon J, et al. IL-33 promotes food anaphylaxis in epicutaneously sensitized mice by targeting mast cells. J Allergy Clin Immunol. 2016;138(5):1356-1366.
7 Silverberg JI. Atopic dermatitis treatment: Current state of the art and emerging therapies. Allergy Asthma Proc. 2017;38(4):243-249.