Developmental Biology - Immune System|
Single Molecule May Explain Allergic Contact Dermatitis
New insight as to what may trigger immune responses to skin creams and commercial products...
Chemical compounds found in skin creams and other personal care products can cause an allergic reaction in our skin, a common condition known as allergic contact dermatitis (ACD). While ACD is on the rise, particularly in industrialized countries, exactly how personal care chemical compounds trigger a reaction remains unknown.
Most allergic reactions involving T cells are attributed to proteins or peptide antigens triggering our immune system. But chemicals found in personal care products (skin creams, shampoo, perfumes) are different kinds of molecules once not thought to directly elicit a reaction by T cells.
Investigators from Brigham and Women's Hospital, Columbia University and Monash University have uncovered a new molecular mechanism by which common components of consumer products can trigger an immune response, highlighting a specific molecular connection that may explain the mystery behind these cases of ACD. The team's findings are published in Science Immunology.
"What we present here is a molecular missing link. We questioned the prevailing paradigm that T cell-mediated allergic reaction is only triggered when T cells respond to proteins or peptide antigens. We found a mechanism through which fragrance can initiate a T cell response through a protein called CD1a."
D. Branch Moody MD, Principal investigator and physician, Brigham University Hospital, Division of Rheumatology, Inflammation and Immunity, and co-author.
For many substances, such as those found in soaps, cosmetics, fragrances, jewelry and plants, it's unclear how a reaction by T cells is triggered. Chemical compounds found in these products were thought to be too small and the wrong chemical structure to be detected directly by T cells, which are immune cells that set off ACD.
Researchers, including co-lead author Annemieke de Jong from Columbia University, wondered if there might be another explanation.
The team tested whether CD1a — a molecule found in immune cells that form the outer layer of human skin — could bind directly to allergens found in personal care products and present these molecules to the immune system, triggering a reaction.
First author, Sarah Nicolai MD, a research fellow in Medicine at Brigham, exposed T cells to material from skin patch testing kits used in allergy clinics to find they respond to certain substances, including balsam of Peru - a tree oil widely used in cosmetics and toothpaste. The team went on to identify substances within balsam of Peru — benzyl benzoate and benzyl cinnamate — directly responsible for stimulating a T cell response. Testing similar substances, they found a dozen small molecules, including farnesol, that appear to generate an immune response.
To understand how these compounds trigger a reaction, investigators at Monash University uncovered the X-ray crystal structure of each. This revealed how farnesol forms a complex with CD1a to kick out naturally occurring human lipids, making CD1a more visible to T cells thus activating it.
While the authors note their work shows fragrances in personal care products can initiate a T cell response, more work is needed to see if they might also cause more severe responses. Researchers need to find out if such patients have T cells that recognize molecules like farnesol. They also look out for new molecules that might block CD1a response, overriding activation of T cells. Work is currently underway to identify promising molecules.
During industrialization, humans have been exposed to increasing numbers of foreign chemicals. Failure of the immune system to tolerate drugs, cosmetics, and other skin products causes allergic contact dermatitis, a T cell–mediated disease with rising prevalence. Models of aB T cell response emphasize T cell receptor (TCR) contact with peptide-MHC complexes, but this model cannot readily explain activation by most contact dermatitis allergens, which are nonpeptidic molecules. We tested whether CD1a, an abundant MHC I–like protein in human skin, mediates contact allergen recognition. Using CD1a-autoreactive human aB T cell clones to screen clinically important allergens present in skin patch testing kits, we identified responses to balsam of Peru, a tree oil widely used in cosmetics and toothpaste. Additional purification identified benzyl benzoate and benzyl cinnamate as antigenic compounds within balsam of Peru. Screening of structurally related compounds revealed additional stimulants of CD1a-restricted T cells, including farnesol and coenzyme Q2. Certain general chemical features controlled response: small size, extreme hydrophobicity, and chemical constraint from rings and unsaturations. Unlike lipid antigens that protrude to form epitopes and contact TCRs, the small size of farnesol allows sequestration deeply within CD1a, where it displaces self-lipids and unmasks the CD1a surface. These studies identify molecular connections between CD1a and hypersensitivity to consumer products, defining a mechanism that could plausibly explain the many known T cell responses to oily substances.
Sarah Nicolai, Marcin Wegrecki, Tan-Yun Cheng, Elvire A. Bourgeois, Rachel N. Cotton, Jacob A. Mayfield, Gwennaëlle C. Monnot, Jérôme Le Nours, Ildiko Van Rhijn, Jamie Rossjohn, D. Branch Moody and Annemieke de Jong.
The authors thank A. G. Kasmar, M. C. Castells, and P. Brennan for advice or critical comments on the manuscript. We thank the staff at the Australian Synchrotron for assistance with data collection and the NIH Tetramer Core Facility for recombinant biotinylated CD1 protein. Funding: S.N. was supported by an NIH training grant (T32 AI007306) and is currently employed by HealthPartners, St. Paul, Minnesota. A.d.J. is supported by a K01 award from the NIH (K01 AR068475) and an Irving Scholarship from the Irving Institute for Clinical and Translational Research at Columbia University. D.B.M. is supported by the NIH (R01 AR048632) and the Wellcome Trust Collaborative Award. This work was supported by the National Health and Medical Research Council of Australia (NHMRC) and the Australian Research Council (ARC) (CE140100011). J.L.N. is supported by an ARC Future Fellowship (FT160100074); J.R. is supported by an Australian ARC Laureate Fellowship and the Wellcome Trust Collaborative Award. Research reported in this publication was performed in the CCTI Flow Cytometry Core, supported, in part, by the Office of the Director, NIH under award S10OD020056. Author contributions: The indicated individuals carried out project oversight and direction (A.d.J., D.B.M., and J.R.); T cell assays (S.N., T.-Y.C., E.A.B., R.N.C., I.V.R., G.C.M., and A.d.J.); protein chemistry, structure, and SPR (M.W. and J.L.N.); and manuscript preparation (S.N., A.d.J., D.B.M., and J.R.) with input from all authors. Competing interests: The authors declare that they have no competing interests. Data and materials availability: Reagents are available to qualified scientists subject to the limitation that cells from primary T cell lines can be limited in number. The data and refined coordinates for the CD1a-farnesol structure were deposited in the Protein Data Bank under accession code 6NUX. All other data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary Materials.
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Jan 17 2020 Fetal Timeline Maternal Timeline News
Chemical compounds found in skin creams and other personal care products
can cause an allergic reaction in the skin. CREDIT Pinterest.