Pertussis toxin alters the innate and the adaptive immune responses in a pertussis-dependent model of autoimmunity.
Pertussis toxin (PTX) is used to promote development of autoimmune diseases. The mechanism(s) are still incompletely understood. We dissected the innate and adaptive immune responses in a PTX-dependent model of autoimmune retinal disease, experimental autoimmune uveoretinitis (EAU), a Th1-driven disease of the neural retina elicited in F344 rats with a peptide derived from the retinal antigen interphotoreceptor retinoid binding protein (IRBP). Our results showed that optimal doses of PTX led to strongly increased innate cytokine responses, followed by enhanced adaptive Th1 immunity and disease. At supraoptimal doses of PTX, EAU was suppressed, the animals exhibited persistent lymphocytosis and had an inhibited chemotactic response to chemokines. We suggest that the suppressive effect of PTX at supraoptimal doses is due to inhibition of lymphocyte emigration from the blood into the target tissue, secondary to inhibition of Gi-protein-coupled chemokine receptor signaling, that persists into the effector phase of disease.
Agarwal
Rajeev K
RK
Laboratory of Immunology, National Eye Institute, National Institutes of Health, 10 Center Drive, 10/10N222, Bethesda, MD 20892-1857, USA.
Sun
Shu Hui
SH
Su
Shao Bo
SB
Chan
Chi-Chao
CC
Caspi
Rachel R
RR
D000222:Adaptation, Physiological / Q000276:immunology; D000818:Animals; D018946:Chemokine CCL5 / Q000276:immunology / Q000494:pharmacology; D054377:Chemokine CXCL12; D018925:Chemokines / Q000276:immunology* / Q000494:pharmacology; D019743:Chemokines, CXC / Q000276:immunology / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology*; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005136:Eye Proteins; D005260:Female; D007107:Immune System / Q000187:drug effects / Q000276:immunology; D007958:Leukocyte Count; D020721:Nervous System Autoimmune Disease, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology; D037342:Pertussis Toxin; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012173:Retinitis / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology; D012177:Retinol-Binding Proteins / Q000276:immunology / Q000494:pharmacology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology*; D014605:Uveitis / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology; D010566:Virulence Factors, Bordetella / Q000276:immunology / Q000494:pharmacology*; D000099214:Retinol-Binding Proteins, Interstitial
D018946:Chemokine CCL5; D054377:Chemokine CXCL12; D018925:Chemokines; D019743:Chemokines, CXC; D016207:Cytokines; D005136:Eye Proteins; D037342:Pertussis Toxin; D012333:RNA, Messenger; D012177:Retinol-Binding Proteins; D010566:Virulence Factors, Bordetella; D000099214:Retinol-Binding Proteins, Interstitial