MyD88 negatively controls hypergammaglobulinemia with autoantibody production during bacterial infection.
A large body of evidence has convincingly shown that Toll-like receptors are necessary sensors for infections with pathogens, but their activation was also suggested to generate autoimmunity. During experimental infections, the lack of these sensors or of their signaling molecules should lead to a deficient immune response. We found out that MyD88, the major adaptor of the Toll/interleukin-1 (Toll/IL-1) receptor signaling pathway, can actually act as a negative regulator of B-cell function in some settings. MyD88-deficient mice infected by Borrelia burgdorferi developed extreme hypergammaglobulinemia compared to wild-type animals, with high levels of immunoglobulin M (IgM) autoantibodies. In vivo, cell transfer experiments and cell blocking assays showed that this phenotype was not linked to the absence of MyD88 in B cells but rather to CD4 T-cell and likely dendritic cell dysfunctions leading to a Th1-to-Th2 cytokine switch. In addition, our results suggest a relative defect in the Ig class switch recombination process, since MyD88 knockout mice developed mostly IgM antibodies. Collectively, these data emphasize the complex role of the Toll/IL-1 receptor pathway in tuning the immune response against infection and avoiding autoimmunity.
Woods
Anne
A
INSERM U737, Hôpital Civil, Strasbourg 67000, France.
Soulas-Sprauel
Pauline
P
Jaulhac
Benoit
B
Arditi
Bérénice
B
Knapp
Anne-Marie
AM
Pasquali
Jean-Louis
JL
Korganow
Anne-Sophie
AS
Martin
Thierry
T
D000818:Animals; D001323:Autoantibodies / Q000378:metabolism*; D001402:B-Lymphocytes / Q000502:physiology; D025065:Borrelia burgdorferi / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006942:Hypergammaglobulinemia / Q000378:metabolism*; D007075:Immunoglobulin M / Q000235:genetics / Q000378:metabolism; D008193:Lyme Disease / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*
D001323:Autoantibodies; D007075:Immunoglobulin M; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D020170:Caspase 1