Summary Background Analyses of circulating chemokines offer novel tools to investigate the T helper (Th)1/Th2 imbalance in allergic disease in vivo. Objective To relate circulating Th1‐ and Th2‐associated chemokines in infancy to allergic disease, sensitization and probiotic supplementation. Methods Circulating levels of Th1‐associated CXC‐chemokine ligand (CXCL)9, CXCL10 and CXCL11 and Th2‐associated CC‐chemokine ligand (CCL)17 and CCL22 were assessed with Luminex and CCL18 with enzyme‐linked immunosorbent assay at birth (n=109), 6 (n=104), 12 (n=116) and 24 months (n=123) in 161 infants completing a double‐blind placebo‐controlled allergy prevention trial with Lactobacillus reuteri during the last month of gestation and through the first year of life. The infants were followed regarding the development of allergic disease and sensitization until 2 years of age. Results The Th2‐associated chemokines CCL17 and CCL22 were the highest at birth and then decreased, whereas CCL18 and the Th1‐associated chemokines increased with age. High Th2‐associated chemokine levels were observed in children developing allergic disease. Sensitization was preceded by elevated levels of the Th2‐associated CCL22 and reduced levels of the Th1‐associated CXCL11 already at birth. The Th2‐associated CCL17 was also elevated at birth in infants developing recurrent wheeze. A high Th2/Th1 ratio (CCL22/CXCL10) at birth associated with both sensitization and eczema development. The presence of L. reuteri in stool in the first week of life was associated with low CCL17 and CCL22 and high CXCL11 levels at 6 months of age. High Th1‐associated chemokine levels were associated with day‐care. Conclusion and Clinical Relevance Allergic disease and sensitization in infancy was associated with low circulating Th1‐ and high Th2‐associated chemokine levels already from birth. Circulating chemokines are useful for investigating the Th1/Th2 imbalance in allergic disease in vivo. Elucidation of the role of chemokines in allergic diseases may lead to future treatments (ClinicalTrials.gov NCT01285830). Cite this as: T. R. Abrahamsson, M. Sandberg Abelius,, A. Forsberg, B. Björkstén and M. C. Jenmalm, Clinical & Experimental Allergy, 2011 (41) 1729–1739.

Exposure to a strong T-helper 2 (Th2)-like environment during fetal development may promote allergy development. Increased cord blood (CB) levels of the Th2-associated chemokine CCL22 were associated with allergy development during the first 2 y of life. The aim of the present study was to determine whether CB Th1-and Th2-associated chemokine levels are associated with allergy development during the first 6 y of life, allowing assessment of respiratory allergic symptoms usually developing in this period. The CB levels of cytokines, chemokines, and total IgE were determined in 56 children of 20 women with allergic symptoms and 36 women without allergic symptoms. Total IgE and allergen-specific IgE antibody levels were quantified at 6, 12, 24 mo, and 6 y of age. Increased CB CCL22 levels were associated with development of allergic sensitization and asthma and increased CCL17 levels with development of allergic symptoms, including asthma. Sensitized children with allergic symptoms showed higher CB CCL17 and CCL22 levels and higher ratios between these Th2-associated chemokines and the Th1-associated chemokine CXCL10 than nonsensitized children without allergic symptoms. A pronounced Th2 deviation at birth, reflected by increased CB CCL17 and CCL22 levels, and increased CCL22/CXCL10 and CCL17/CXCL10 ratios might promote allergy development later in life. (Pediatr Res 70: 495-500, 2011)

Ro52 (TRIM21)is an E3 ligase of the tripartite motif family that negatively regulates proinflammatory cytokine production by ubiquitinating transcription factors of the interferon regulatory factor family. Autoantibodies to Ro52 are present in patients with lupus and Sjögren's syndrome, but it is not known if these autoantibodies affect the function of Ro52. To address this question, the requirements for Ro52 E3 ligase activity were first analyzed in detail. Scanning a panel of E2 ubiquitin-conjugating enzymes, we found that UBE2D1-4 and UBE2E1-2 supported the E3 ligase activity of Ro52 and that the E3 ligase activity of Ro52 was dependent on its RING domain. We also found that the N-terminal extensions in the class III E2 enzymes affected their interaction with Ro52. Although the N-terminal extension in UBE2E3 made this E2 enzyme unable to function together with Ro52, the N-terminal extensions in UBE2E1 and UBE2E2 allowed for a functional interaction with Ro52. AntiRo52-positive patient sera and affinity-purified anti-RING domain autoantibodies inhibited the E3 activity of Ro52 in ubiquitination assays. Using NMR, limited proteolysis, ELISA, and Ro52 mutants, we mapped the interactions between Ro52, UBE2E1, and anti-Ro52 autoantibodies. We found that antiRo52 autoantibodies inhibited the E3 ligase activity of Ro52 by sterically blocking the E2/E3 interaction between Ro52 and UBE2E1. Our data suggest that anti-Ro52 autoantibodies binding the RING domain of Ro52 may be actively involved in the pathogenesis of rheumatic autoimmune disease by inhibiting Ro52-mediated ubiquitination.Ro52 (TRIM21) is an interferon-inducible protein frequently targeted by autoantibodies in patients with primary Sjögren's syndrome (SS) 4 and systemic lupus erythematosus (SLE) (1, 2). As a member of the tripartite motif (TRIM) protein family (3), Ro52 is characterized by a RING domain (4), a B-box type 2 motif (5), and a coiled-coil region. A B30.2 domain is located in the C-terminal region (6). Several TRIM family members, including Ro52, have been identified as E3 ubiquitin ligases involved in the ubiquitination process (7-10). Ubiquitination is a covalent post-translational modification of proteins by the 76-amino acid residue polypeptide ubiquitin, leading either to proteolysis in the proteasome, internalization from membranes, or functional alteration (11,12). After activation by a ubiquitin-activating enzyme (E1), ubiquitin is transferred to a ubiquitin-conjugating enzyme (E2) followed by a ubiquitin ligase (E3)-mediated transfer of ubiquitin from the E2 to a target protein (13). Ro52 mediates ubiquitination of several members of the interferon regulatory factor (IRF) transcription factor family, thereby regulating cytokine production (14 -17). Gene disruption of Ro52 leads to increased production of proinflammatory cytokines by embryonic fibroblasts and immune cells after Toll-like receptor activation, suggesting that Ro52 negatively regulates IRF activity (16,17).Autoantibodies to Ro52 can appear years before tissue damage is ...

Problem: How maternal allergy affects the systemic and local immunological environment during pregnancy and the immune development of the offspring is unclear.Method of study: Expression of 40 genes was quantified by PCR arrays in placenta, PBMC and CBMC from 7 allergic and 12 non-allergic women and their offspring. Results

Abelius MS, Lempinen E, Lindblad K, Ernerudh J, Berg G, Matthiesen L, Nilsson LJ, Jenmalm MC Th2-like chemokine levels are elevated in allergic children and influenced by maternal immunity during pregnancy Pediatr Allergy Immunol. Background:The influence of the intrauterine environment on the immunity and allergy development in the offspring is unclear. We aimed to investigate (i) if the pregnancy magnifies the Th2 immunity in allergic and non-allergic women, (ii) if the maternal chemokine levels during pregnancy influenced the offspring's chemokine levels during childhood and (iii) the relationship between circulating Th1/Th2-associated chemokines and allergy in mothers and children.

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Pregnancy had a clear effect on the allergen-induced IL-5, IL-13, CCL17, IFN-γ and CXCL10 production, with distinct enhanced Th2-responses to birch in the allergic group and to cat in the non-allergic group.

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