It has been shown recently that MCs are required for differential regulation of the immune response by granulocytic versus monocytic MDSCs. Granulocytic MDSCs promoted parasite clearance, whereas monocytic MDSCs enhanced tumor progression; both activities were abrogated in MC-deficient mice. Herein, we demonstrate that the lack of MCs also influences MDSC trafficking. Preferential trafficking to the liver was not seen in MC-deficient mice. In addition, evidence that the MC mediator histamine was important in MDSC trafficking and activation is also shown. MDSCs express HR1-3. Blockade of these receptors by HR1 or HR2 antagonists reversed the histamine enhancement of MDSC survival and proliferation observed in cell culture. In addition, histamine differentially influenced Arg1 and iNOS gene expression in MDSCs and greatly enhanced IL-4 and IL-13 message, especially in granulocytic MDSCs. Evidence that histamine influenced activity seen in vitro translated to in vivo when HR1 and HR2 antagonists blocked the effect of MDSCs on parasite expulsion and tumor metastasis. All of these data support the MDSC-mediated promotion of Th2 immunity, leading to the suggestion that allergic-prone individuals would have elevated MDSC levels. This was directly demonstrated by looking at the relative MDSC levels in allergic versus control patients. Monocytic MDSCs trended higher, whereas granulocytic MDSCs were increased significantly in allergic patients. Taken together, our studies indicate that MCs and MC-released histamine are critical for MDSC-mediated immune regulation, and this interaction should be taken into consideration for therapeutic interventions that target MDSCs.

B cell ADAM10 is required for the development and maintenance of proper secondary lymphoid tissue architecture; however, the underlying mechanism remains unclear. In this study, we show disturbances in naïve lymph node architecture from B cell specific ADAM10 deficient mice (ADAM10B−/−) including loss of B/T compartmentalization, attenuation of FDC reticula, excessive collagen deposition, and increased HEV formation. Because TNFα signaling is critical for secondary lymphoid tissue architecture, we examined compensatory changes in ADAM17 and TNFα in ADAM10B−/− B cells. Surprisingly, defective follicular development in these mice was associated with increased rather than decreased TNFα expression. Here, we describe an increase in TNFα message, mRNA stability, soluble protein release, and membrane expression in ADAM10B−/− B cells compared to WT, which coincides with increased ADAM17 message and protein. To assess the mechanistic contribution of excessive TNFα to abnormal lymphoid architecture in ADAM10B−/− mice, we performed a bone marrow reconstitution study. Rectification of WT architecture was noted only in irradiated WT mice reconstituted with ADAM10B−/− + TNFKO bone marrow due to normalization of TNFα levels not seen in ADAM10B−/− alone. We conclude that ADAM17 overcompensation causes excessive TNFα shedding and further upregulation of TNFα expression, creating an aberrant signaling environment within B cell cortical regions of ADAM10B−/− lymph nodes, highlighting a key interplay between B cell ADAM10 and ADAM17 with respect to TNFα homeostasis.

Among 23 patients carrying methicillin-resistant Staphylococcus aureus (MRSA) in their anterior nares, 6 (26%) also carried methicillin-susceptible S. aureus (MSSA) as less prevalent flora. In 4 of the 6 patients, the MSSA was unrelated to prevalent MRSA, as determined by pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), and staphylococcal protein A (spa) typing. However, in two patients, the strains were identical except for the absence of spontaneous staphylococcal cassette chromosome mec (SCCmec). We consider this evidence of spontaneous SCCmec excision in vivo.

ADAM10 is required for the development and maintenance of proper secondary lymphoid tissue architecture and optimal Ig class-switching; however, the underlying mechanisms remain unclear. TNFα is cleaved by ADAM10 and ADAM17; and, the aberrant lymphoid tissue architecture noted in B cell specific ADAM10 deficient mice (ADAM10B-/-) resembles that of global TNFα knockouts prompting analysis of TNFα production in these mice. Our results indicated that ADAM10B-/- B cells stimulated with LPS/IL4 or anti-CD40/IL4 showed increased levels of soluble and membrane bound TNFα compared to WT, which was confirmed by qPCR and immunohistochemistry of naïve lymph nodes. In addition, ADAM17 expression, assessed by qPCR, was increased in stimulated ADAM10B-/- B cells, suggesting ADAM17 overcompensation. In contrast, stimulated ADAM10B-/- B cells exhibited impaired proliferation and activation as indicated by decreased 3H-thymidine incorporation and less B220 upregulation respectively. We reason that ADAM17 overcompensation generates aberrant TNFα signaling and enhanced TNFα expression in stimulated ADAM10B-/- B cells; however, other ADAM17 substrates may be involved and are currently under investigation. In conclusion, this work institutes a key interplay between ADAM10, ADAM17, and B cell-TNFα with critical implications in autoimmune pathogenesis and therapeutics where deliberate inhibition of one ADAM may be accompanied by upregulation of another, resulting in unintended consequences.