Terminal B cell differentiation is skewed by deregulated interleukin-6 secretion in beta2 integrin-deficient mice.
Absence of the common beta chain (CD18) of beta(2) integrins leads to leukocyte-adhesion deficiency type-1 (LAD1) in humans. Mice with a CD18 null mutation suffer from recurrent bacterial infections, impaired wound healing, and skin ulcers, closely resembling human LAD1. Previous findings in CD18(-/-) mice demonstrated a skewed terminal B cell differentiation with plasmacytosis and elevated serum immunoglobulin G (IgG). As interleukin-6 (IL-6) is a potent enhancer of plasma cell formation and Ig secretion, we assessed IL-6 serum levels of CD18(-/-) and wild-type (WT) mice kept under a conventional or barrier facility or specific pathogen-free (SPF) conditions. We detected an up to 20-fold increase in IL-6 in serum of CD18(-/-) mice compared with WT controls when kept under conventional or barrier facility conditions, respectively. Under SPF conditions, no significant differences in terms of IL-6 serum levels were found between CD18(-/-) and WT mice. However, histological alterations of secondary lymphoid tissues, plasmacytosis, abnormal plasmacytoid cells (Mott cells), and hypergammaglobulinemia persisted. To further analyze the role of IL-6 in these pathological alterations, we established a CD18(-/-) IL-6(-/-) double-deficient mouse mutant. In these mice, serum IgG levels were normal, and the altered plasma cell phenotype, including Mott cells, was no longer detectable. The CD18(-/-) IL-6(-/-) double-deficient mouse model thus demonstrated that IL-6 is responsible for parts of the phenotype seen in the CD18(-/-) mouse mutants. It may be of interest to examine human leukocyte-adhesion deficiency type-1 patients closer and search for pathological changes possibly induced via overproduction of IL-6.
Peters
Thorsten
T
Department of Dermatology, and Allergic Diseases, University of Ulm, Maienweg 12, 89081 Ulm, Germany.
Bloch
Wilhelm
W
Wickenhauser
Claudia
C
Tawadros
Samir
S
Oreshkova
Tsvetelina
T
Kess
Daniel
D
Krieg
Thomas
T
Müller
Werner
W
Scharffetter-Kochanek
Karin
K
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018821:CD18 Antigens / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D015850:Interleukin-6 / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D018821:CD18 Antigens; D007074:Immunoglobulin G; D015850:Interleukin-6; D008070:Lipopolysaccharides