In the Galli Lab, we study...

Regulation of mast cell and basophil development and function.

The papers and images below are representatives of our research using imaging approaches to monitor mast cell and basophil degranulation/activation in vitro and in vivo:

1. Reber LL, Sibilano R*, Starkl P* (*contributed equally), Roers A, Grimbaldeston MA, Tsai M, Gaudenzio N**, Galli SJ** (**co-corresponding authors). Imaging protective mast cells in living mice during severe contact hypersensitivity. JCI Insight. 2017 May 4;2(9). pii: 92900. doi: 10.1172/jci.insight.92900. [Epub ahead of print] PubMed PMID: 28469089; PubMed Central PMCID: PMC5414565.

A single injection of fluorochrome-labeled avidin enables specific labeling of dermal mast cell intracellular secretory granules.

2. Mukai K, Chinthrajah RS, Nadeau KC, Tsai M, Gaudenzio N*, Galli SJ* (*contributed equally). A new fluorescent-avidin-based method for quantifying basophil activation in whole blood. J Allergy Clin Immunol. 2017 Jun 9. pii: S0091-6749(17)30927-2. doi:10.1016/j.jaci.2017.03.052. [Epub ahead of print] PubMed PMID: 28606590.

Anti-IgE challenge increases the binding of fluorochrome-labeled avidin to human blood basophils

3. Gaudenzio N, Sibilano R*, Marichal T* (contributed equally), Starkl P, Reber LL, Cenac N, McNeil BD, Dong X, Hernandez JD, Sagi-Eisenberg R, Hammel I, Roers A, Valitutti S, Tsai M, Espinosa E**, Galli SJ** (**co-corresponding authors). Different activation signals induce distinct mast cell degranulation strategies. J Clin Invest. 2016 Oct 3;126(10):3981-3998. doi:10.1172/JCI85538. Epub 2016 Sep 19. PubMed PMID: 27643442; PubMed Central PMCID: PMC5096814.

Video: Human MC activation by substance P (SP) or anti-IgE induces distinct [Ca2+] signaling and degranulation dynamics.

Model of distinct “innate” (A) or “adaptive” (B) patterns of MC degranulation in response to (A) Substance P, C3a, C5a, or endothelin 1 (ET1) versus (B) anti-IgE or IgG immune complexes

Regulation of Type 2 immune responses in host defense, such as parasite resistance, or in diseases, such as allergic reactions in asthma, atopic dermatitis, anaphylaxis, food allergy, etc.

We investigate both the harmful effects of mast cells and basophils and the beneficial roles of these cells in host defense.  Representative recent studies are listed below:

1. Mukai K, Karasuyama H, Kabashima K, Kubo M, Galli SJ. Differences in the Importance of Mast Cells, Basophils, IgE, and IgG versus That of CD4(+) T Cells and ILC2 Cells in Primary and Secondary Immunity to Strongyloides venezuelensis. Infect Immun. 2017 Apr 21;85(5). pii: e00053-17. doi: 10.1128/IAI.00053-17. Print. 2017 May. PubMed PMID: 28264908; PubMed Central PMCID: PMC5400847.

2. Sibilano R, Gaudenzio N, DeGorter MK, Reber LL, Hernandez JD, Starkl PM, Zurek OW, Tsai M, Zahner S, Montgomery SB, Roers A, Kronenberg M, Yu M*, Galli SJ* (*co-corresponding authors). A TNFRSF14-FcɛRI-mast cell pathway contributes to development of multiple features of asthma pathology in mice. Nat Commun. 2016 Dec 16;7:13696. doi:10.1038/ncomms13696. PubMed PMID: 27982078; PubMed Central PMCID: PMC5171877.

3. Reber LL, Marichal T, Mukai K, Kita Y, Tokuoka SM, Roers A, Hartmann K, Karasuyama H, Nadeau KC, Tsai M, Galli SJ. Selective ablation of mast cells or basophils reduces peanut-induced anaphylaxis in mice. J Allergy Clin Immunol. 2013 Oct;132(4):881-8.e1-11. doi: 10.1016/j.jaci.2013.06.008. Epub 2013 Aug 1. PubMed PMID: 23915716; PubMed Central PMCID: PMC3794715.

Roles of mast cells and IgE in innate and adaptive immune resistance to the toxicity of venoms.

We investigate how the innate functions of mast cells, particularly degradation of venom toxins by mast cell-derived proteases, can enhance resistance to certain arthropod or reptile venoms. In addition, our recent work in mice shows that the acquired Th2 immune responses (associated with the production of IgE antibodies) induced by Russell's viper venom or honeybee venom can increase the resistance of mice to challenge with potentially lethal doses of either of the venoms. In contrast to the detrimental effects associated with allergic type 2 (Th2) immune responses, our findings support the conclusion that mast cells and IgE-dependent immune responses to venoms can contribute to innate and adaptive resistance to venom-induced pathology and mortality.

1. Starkl P*, Marichal T* (*co-first authors), Gaudenzio N, Reber LL, Sibilano R, Tsai M, Galli SJ. IgE antibodies, FcεRIα, and IgE-mediated local anaphylaxis can limit snake venom toxicity. J Allergy Clin Immunol. 2016 Jan;137(1):246-257.e11. doi:10.1016/j.jaci.2015.08.005. Epub 2015 Sep 26. PubMed PMID: 26410782; PubMed Central PMCID: PMC4715494.

2. Marichal T*, Starkl P* (*co-first authors), Reber LL, Kalesnikoff J, Oettgen HC, Tsai M, Metz M**, Galli SJ** (**co-corresponding authors). A beneficial role for immunoglobulin E in host defense against honeybee venom. Immunity. 2013 Nov 14;39(5):963-75. doi: 10.1016/j.immuni.2013.10.005. Epub 2013 Oct 24. PubMed PMID: 24210352; PubMed Central PMCID: PMC4164235.

Th2 immunity, IgE, and FcεRI can enhance mouse resistance to honeybee venom

Role of RABGEF1 in skin homeostasis and epidermal barrier function.

RAB guanine nucleotide exchange factor 1 (RABGEF1), also known as RABEX-5, is a multifunctional protein containing an A20-like zinc finger domain exhibiting E3 ubiquitin ligase activity and a central Vps9 domain, which promotes GEF activity for the endocytic pathway regulator RAB5. We characterized RABGEF1 as a negative regulator of mast cell activation in vitro and a critical regulator of skin homeostasis in mice (Tam S-Y, Tsai M, et al. Nat Immunol 2004 Aug;5(8):844-52) and subsequently identified keratinocyte-intrinsic RABGEF1 as a critical regulator of skin homeostasis (Marichal T, Gaudenzio N, et al. J Clin Invest. 2016 Dec 1;126(12):4497-4515). We showed that RABGEF1 can control the activation threshold of keratinocytes and limit IL-1R/MYD88–dependent signaling pathways, MYD88-dependent barrier dysfunction, and skin inflammation. Abnormalities in keratinocyte RABGEF1 expression can occur at sites of allergic skin inflammation in mice and humans (Marichal T, Gaudenzio N, et al. J Clin Invest. 2016 Dec 1;126(12):4497-4515), and may therefore contribute to the impairment of skin barrier function in such settings.

Marichal T*, Gaudenzio N* (*co-first authors), El Abbas S, Sibilano R, Zurek O, Starkl P, Reber LL, Pirottin D, Kim J, Chambon P, Roers A, Antoine N, Kawakami Y, Kawakami T, Bureau F, Tam SY, Tsai M, Galli SJ. Guanine nucleotide exchange factor RABGEF1 regulates keratinocyte-intrinsic signaling to maintain skin homeostasis. J Clin Invest. 2016 Dec 1;126(12):4497-4515. doi: 10.1172/JCI86359. Epub 2016 Nov 7. PubMed PMID: 27820702; PubMed Central PMCID: PMC5127679.

A deficiency of RABGEF1 in keratinocytes can lead to atopic dermatitis-like skin lesion in mice