This study was designed to determine if cigarette smoking adversely affects functional recovery following ischemia/reperfusion (I/R) injury in peripheral nerves. Forty Wistar rats were divided evenly among four groups. Animals in groups A and B were exposed to cigarette smoke via a controlled smoking chamber for 20 minutes daily. On study day 14, all animals underwent a controlled I/R injury to one sciatic nerve. Recovery was assessed with walking track assessments, malondialdehyde (MDA) assay, and histology. Walking track results on study day 21 did not differ significantly between the smoking and nonsmoking animals. However, by study day 28, the nonsmoking animals showed a greater degree of functional recovery (SFI = -18.0 and -22.8, respectively, P = 0.03). MDA concentration in the smoking group was significantly higher than the nonsmoking group at the 28 day time point (P = 0.04). Exposure to cigarette smoke was associated with a slower functional recovery following peripheral nerve I/R injury.

Invasive group A streptococcus (GAS) infections include necrotizing soft tissue infections (NSTI) and streptococcal toxic shock syndrome (STSS). We have previously shown that host HLA class II allelic variations determine the risk for necrotizing fasciitis (NF), a dominant subgroup of NSTI, and STSS by modulating responses to GAS superantigens (SAgs). SAgs are pivotal mediators of uncontrolled T-cell activation, triggering a proinflammatory cytokine storm in the host. FoxP3-expressing CD4 CD25 T regulatory cells (Tregs) comprise phenotypically and functionally heterogeneous subsets with a profound ability to suppress inflammatory responses. Specifically, activated Tregs, which express glycoprotein A repetitions predominant (GARP) and display latent transforming growth factor β1 (TGF-β1) complexes (latency-associated peptide [LAP]), exhibit strong immunosuppressive functions. The significance of Tregs that may participate in suppressing inflammatory responses during NSTI is unknown. Here, we phenotypically characterized FoxP3/GARP/LAP-expressing Tregs in GAS-infected or SAg (SmeZ)-stimulated splenocytes from transgenic (tg) mice expressing human HLA-II DRB1*15 (DR15 allele associated with nonsevere NF/STSS-protective responses) or DRB1*0402/DQB1*0302 (DR4/DQ8 alleles associated with neutral risk for combined NF/STSS). We demonstrated both and that the neutral-risk allele upregulates expression of CD4 CD25 activated effector T cells, with a significantly lower frequency of Foxp3/GARP LAP but higher frequency of Foxp3 LAP Tregs than seen with the protective allele. Additional studies revealed that the presentation of SmeZ by the neutral-risk allele significantly increases proliferation and expression of effector cytokines gamma interferon (IFN-γ) and interleukin-2 (IL-2) and upregulates CD4 CD25 T cell receptors (TCRs) carrying specific Vβ 11 chain (TCRVβ11) T cells and Th1 transcription factor mRNA levels. Our data suggest that neutral-risk alleles may drive Th1 differentiation while attenuating the induction of Tregs associated with suppressive function.

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