Hyperactivated MyD88 signaling in dendritic cells, through specific deletion of Lyn kinase, causes severe autoimmunity and inflammation

Abstract

Significance The pathogenesis of systemic lupus erythematosus, a complex autoimmune inflammatory disease triggered by genetic and environmental factors, is generally attributed to defects in lymphocyte function. We show that dendritic cells (DCs) also drive autoimmune disease in mice. Our observations that dysregulation of Toll-like receptor signaling (a key pathway that alerts the immune system of encounter with infectious agents) in DCs alone is sufficient to induce autoimmunity sheds new light on the pathogenesis of this disease. This work implies that DC-specific reduction of Toll-like receptor signaling may prove to be a highly specific approach to reduce the symptoms of autoimmune diseases.

Irgm1 coordinately regulates autoimmunity and host defense at select mucosal surfaces

“…In other settings, MyD88 has been shown to support TLR7-dependent induction of type I IFNs by pDCs (39), BAFF production by and signaling in B cells (40,41), as well as several B cell functions including autoantibody production (42). Hyperactivated MyD88-dependent signaling in DCs is sufficient to cause autoimmune disease in mice (20). Taking these results together, we thus propose that enhanced MyD88-dependent signaling in select interacting cell types of the Irgm1 -/-mouse may promote an axis of IFN overproduction, downstream BAFF induction, and BAFF hypersensitivity, leading to autoimmunity.…”

“…The lymphocytic infiltration of several exocrine tissues in Irgm1 -/-mice was reminiscent of human autoimmune disease, SS in particular. Given this, we tested Irgm1 -/-serum for the presence of anti-nuclear antibodies (ANAs) using HEp-2 cells as substrate, a classical indirect immunofluorescence procedure used in clinical medicine (and mouse models) to screen for autoantibodies targeting nuclear antigens (20). Of interest, although IgG class ANAs were not detected in Irgm1 -/-(or WT) serum, an abnormal increase in IgA ANA was evident, yielding nuclear staining in a coarse speckled pattern ( Figure 5A).…”

Infectivity and insertional mutagenesis of endogenous retrovirus in autoimmune NZB and B/W mice

“…This, in turn, results in proliferative disease, which accelerates the lupus-like disease (Drappa et al, 1993). Lack of tolerance also happens in non-autoimmune mice that (i) have a mutation leading to hyperreactive external calcium entry in B-cells (Yu et al, 2005), (ii) are overexpressing B-cell activators, including BAFF (Mackay et al, 1999), or (iii) are deficient (knockout) in inhibitors, including CD22 (Nitschke et al, 1997;O'Keefe et al, 1996;Otipoby et al, 1996;Sato et al, 1996), Lyn (Hibbs et al, 1995;Lamagna et al, 2013Lamagna et al, , 2014 and Fcc RIIb (Bolland & Ravetch, 2000). Similarly, we suggest that insertional mutagenesis may accelerate lupus in B/W mice.…”

Oxygen Increases Lung Inflammatory Response in Spontaneous One-Lung Ventilation in Rabbits: A Prospective Randomized Experimental Study

“…Infrequent inflammatory cells and/or inflammation confined to a few areas (corresponding to less than 15 cells per high magnification field of 40×) [15] were defined as a light inflammatory response. Multiple areas in the tissue or a large area of inflammatory cells (corresponding to an average of 16 to 25 cells per high magnification field 40×) [15] were defined as a moderate inflammatory response.…”

“…Multiple areas in the tissue or a large area of inflammatory cells (corresponding to an average of 16 to 25 cells per high magnification field 40×) [15] were defined as a moderate inflammatory response. Large multifocal areas of tissue with inflammatory cells or almost all areas of tissue affected (corresponding to more than 25 cells per high magnification field 40×) [15] were defined as severe inflammation. Thus, plates were classified as light, moderate or severe inflammatory responders according to the intensity of inflammation assessed.…”