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The objective of the present research was to expand upon previous findings indicating that military sexual trauma interacts with combat exposure to predict PTSD among female Iraq/Afghanistan-era veterans. Three hundred and thirty female veterans completed self-report measures of combat experiences, military sexual assault (MSA) experiences, and PTSD symptoms as well as structured diagnostic interviews for PTSD. A significant strength of the present research was the use of PTSD diagnosis as an outcome measure. Consistent with prior research, both combat exposure and MSA were significant predictors of PTSD symptoms (linear regression) and PTSD diagnoses (logistic regression). Specifically, participants who experienced deployment-related MSA had approximately six times the odds of developing PTSD compared to those who had not experienced deployment-related MSA, over and above the effects of combat exposure. Contrary to expectations, the hypothesized interaction between MSA and combat exposure was not significant in any of the models. The low base rate of MSA may have limited power to find a significant interaction; however, these findings are also consistent with other recent studies that have failed to find support for the hypothesized interaction. Thus, whereas the majority of available evidence indicates that MSA increases risk for PTSD among veterans over and above the effects of combat, there is presently only limited support for the hypothesized MSA x combat interaction. These findings highlight the continued need for prevention and treatment of MSA in order to improve veterans' long-term mental health and well-being.

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PURPOSE: Aggressive driving contributes to the high rates of postdeployment motor vehicle-related injury and death observed among veterans, and veterans cite problems with anger, aggressive driving, and road rage as being among their most pressing driving-related concerns. Both posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) have been associated with driving-related deficits in treatment-seeking samples of veterans, but the relative contribution of each of these conditions to problems with aggressive driving in the broader population of combat veterans is unclear. METHOD: χ2 and logistic regression analyses were used to examine the relative association of PTSD, TBI, and co-occurring PTSD and TBI to self-reported problems with road rage in a sample of 1,102 veterans living in the mid-Atlantic region of the United States who had served in Afghanistan or Iraq. RESULTS: Results indicate that controlling for relevant demographic variables, PTSD without TBI (odds ratio = 3.44, p < .001), and PTSD with co-occurring TBI (odds ratio = 4.71, p < .001) were associated with an increased risk of road rage, but TBI without PTSD was not. CONCLUSIONS: Our findings suggest that PTSD, with or without comorbid TBI, may be associated with an increased risk of aggressive driving in veterans. Clinical implications for treating problems with road rage are discussed, including use of interventions targeting hostile interpretation bias and training in emotional and physiological arousal regulation skills. (PsycINFO Database Record

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The TLR5 agonist flagellin induces innate and adaptive immune responses in a MyD88-dependent manner and is under development as a vaccine adjuvant. In vitro studies indicate that, compared with other bacteria-derived adjuvants, flagellin is a very potent activator of proinflammatory gene expression and cytokine production from cells of nonhemopoietic origin. However, the role of nonhemopoietic cells in promoting flagellin-induced immune responses in vivo remains unclear. To investigate the relative contributions of the nonhemopoietic (radioresistant) and the hemopoietic (radiosensitive) compartments, we measured both innate and adaptive immune responses of flagellin-treated MyD88 radiation bone marrow chimeras. We observed that radiosensitive and radioresistant cells played distinct roles in the innate response to flagellin, with the radiosensitive cells producing the majority of the TNF-alpha, IL-12, and IL-6 cytokines and the radioresistant cells most of the KC, IP-10, and MCP-1 cytokines. Direct activation of either compartment alone by flagellin initiated dendritic cell costimulatory molecule up-regulation and induced a significant humoral immune response to the protein itself as well as to coinjected OVA. However, robust humoral responses were only observed when MyD88 was present in both cell compartments. Further studies revealed that hemopoietic and nonhemopoietic expression of the cytokines TNF-alpha and IL-6, but not IL-1, played an important role in promoting flagellin-induced Ab responses. Thus, in vivo both radioresistant and hemopoietic cells play key nonredundant roles in mediating innate and adaptive immune responses to flagellin.

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Gut barrier dysfunction may occur in short bowel syndrome (SBS). We hypothesized that systemic exposure to flagellin and lipopolysaccharide (LPS) in SBS might regulate specific immune responses. We analyzed serial serum samples obtained from parenteral nutrition (PN)-dependent patients with SBS versus non-SBS control serum. Serum from 23 adult SBS patients was obtained at baseline and 4, 8, 12, 16, 20, and 24 wk in a trial of modified diet with or without growth hormone. Control serum was obtained from 48 healthy adults and 37 adults requiring PN during critical illness. Serum flagellin was detected by an ELISA recognizing an array of gram-negative flagellins, and LPS was detected by limulus assay. Serum flagellin- and LPS-specific immunoglobulin levels (IgM, IgA, and IgG) were determined by ELISA. Serum flagellin and LPS were undetectable in control subjects. In contrast, serum flagellin, LPS, or both were detected in 14 SBS patients (61%) during one or more time points [flagellin alone, 5/23 (22%); LPS alone, 6/23 (26%); or flagellin + LPS, 3/23 (13%)]. Flagellin-specific serum IgM, IgA, and IgG levels were markedly increased in SBS patients compared with both control populations and remained elevated during the 6-mo study period. LPS-specific IgA was significantly higher in SBS patients compared with healthy controls; LPS-specific IgM, IgA, and IgG levels each decreased over time in association with PN weaning. We conclude that adults with PN-dependent SBS are systemically exposed to flagellin and LPS, presumably from the gut lumen. This likely regulates innate and adaptive immune responses to these specific bacterial products.

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Bacterial flagellin, the primary structural component of flagella, is a dominant target of humoral immunity upon infection by enteric pathogens and in Crohn's disease. To better understand how such responses may be regulated, we sought to define, in mice, basic mechanisms that regulate generation of flagellin-specific Igs. We observed that, in response to i.p. injection with flagellin, generation of flagellin-specific Ig required activation of innate immunity in that these responses were ablated in MyD88-deficient mice and that flagellin from Helicobacter pylori, which is known not to activate TLR5, also did not elicit Abs. Mice lacking alphabeta T cells (TCRbeta(null)) were completely deficient in their ability to make flagellin Abs in various contexts indicating that, in contrast to common belief, generation of flagellin-specific Ig is absolutely T cell dependent. In contrast to Ab responses to whole flagella (H serotyping), responses to flagellin monomers displayed only moderate serospecificity. Whereas neither oral nor rectal administration of flagellin elicited a strong serum Ab response, induction of colitis with dextran sodium sulfate resulted in a MyD88-dependent serum Ab response to endogenous flagellin, suggesting that, in an inflammatory milieu, TLR signaling promotes acquisition of Abs to intestinal flagellin. Thus, acquisition of a humoral immune response to flagellin requires activation of innate immunity, is T cell dependent, and can originate from flagellin in the intestinal tract in inflammatory conditions in the intestine.

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Crohn's disease (CD) is driven by seemingly aberrant immune responses directed toward commensal enteric microflora. However, the specific antigens targeted by this immune response remain largely undefined. Herein, we demonstrate that common enteric flagellins are one such target of the CD-associated immune response. Thus flagellin may not only drive acute inflammation via activation of Toll-like receptor 5-mediated gene expression but may also serve as a target of the adaptive immune response that maintains the chronic inflammation characteristic of CD.

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