IL-22 regulates lymphoid chemokine production and assembly of tertiary lymphoid organs.
The series of events leading to tertiary lymphoid organ (TLO) formation in mucosal organs following tissue damage remain unclear. Using a virus-induced model of autoantibody formation in the salivary glands of adult mice, we demonstrate that IL-22 provides a mechanistic link between mucosal infection, B-cell recruitment, and humoral autoimmunity. IL-22 receptor engagement is necessary and sufficient to promote differential expression of chemokine (C-X-C motif) ligand 12 and chemokine (C-X-C motif) ligand 13 in epithelial and fibroblastic stromal cells that, in turn, is pivotal for B-cell recruitment and organization of the TLOs. Accordingly, genetic and therapeutic blockade of IL-22 impairs and reverses TLO formation and autoantibody production. Our work highlights a critical role for IL-22 in TLO-induced pathology and provides a rationale for the use of IL-22-blocking agents in B-cell-mediated autoimmune conditions.
Rheumatology Research Group, Centre for Translational Inflammation Research, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, B15 2TT, United Kingdom; University of Birmingham Research Laboratories, Queen Elizabeth Hospital, Birmingham, B15 2WD, United Kingdom; f.barone@bham.ac.uk.
Francesca
F
Barone
Rheumatology Research Group, Centre for Translational Inflammation Research, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, B15 2TT, United Kingdom; University of Birmingham Research Laboratories, Queen Elizabeth Hospital, Birmingham, B15 2WD, United Kingdom;
Saba
S
Nayar
Rheumatology Research Group, Centre for Translational Inflammation Research, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, B15 2TT, United Kingdom; University of Birmingham Research Laboratories, Queen Elizabeth Hospital, Birmingham, B15 2WD, United Kingdom;
Joana
J
Campos
Rheumatology Research Group, Centre for Translational Inflammation Research, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, B15 2TT, United Kingdom; University of Birmingham Research Laboratories, Queen Elizabeth Hospital, Birmingham, B15 2WD, United Kingdom;
Thomas
T
Cloake
School of infection and Immunity, College of Medical and Dental Sciences, University of Birmingham, B15 2TT, United Kingdom;
David R
DR
Withers
School of infection and Immunity, College of Medical and Dental Sciences, University of Birmingham, B15 2TT, United Kingdom;
Kai-Michael
KM
Toellner
School of infection and Immunity, College of Medical and Dental Sciences, University of Birmingham, B15 2TT, United Kingdom;
Yang
Y
Zhang
Pfizer Research, Cambridge MA 02139-3526;
Lynette
L
Fouser
Rheumatology Research Group, Centre for Translational Inflammation Research, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, B15 2TT, United Kingdom; University of Birmingham Research Laboratories, Queen Elizabeth Hospital, Birmingham, B15 2WD, United Kingdom;
Benjamin
B
Fisher
Rheumatology Research Group, Centre for Translational Inflammation Research, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, B15 2TT, United Kingdom; University of Birmingham Research Laboratories, Queen Elizabeth Hospital, Birmingham, B15 2WD, United Kingdom;
Simon
S
Bowman
Division of Allergy, Immunology and Rheumatology, Department of Medicine, University of Rochester, Rochester, NY 14642;
Javier
J
Rangel-Moreno
Division of Allergy, Immunology and Rheumatology, Department of Medicine, University of Rochester, Rochester, NY 14642;
Maria de la Luz
Mde L
Garcia-Hernandez
Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294-2182;
Troy D
TD
Randall
Centre for Experimental Medicine and Rheumatology, Queen Mary University of London, EC1M 6BQ, London United Kingdom;
Davide
D
Lucchesi
Centre for Experimental Medicine and Rheumatology, Queen Mary University of London, EC1M 6BQ, London United Kingdom;
Michele
M
Bombardieri
Centre for Experimental Medicine and Rheumatology, Queen Mary University of London, EC1M 6BQ, London United Kingdom;
Costantino
C
Pitzalis
Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
Sanjiv A
SA
Luther
Rheumatology Research Group, Centre for Translational Inflammation Research, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, B15 2TT, United Kingdom; University of Birmingham Research Laboratories, Queen Elizabeth Hospital, Birmingham, B15 2WD, United Kingdom;
Christopher D
CD
Buckley
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000378:metabolism; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000502:physiology*; D008221:Lymphoid Tissue / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000097043:Interleukin-22
D001323:Autoantibodies; D019743:Chemokines, CXC; D007378:Interleukins; D000097043:Interleukin-22
IL-22; Sjogren's syndrome; autoimmunity; chemokines; tertiary lymphoid organs