Group differences in proneness to inflammation

Pennington, Renee; Gatenbee, Chandler D.; Kennedy, Brett; Harpending, Henry; Cochran, Gregory

doi:10.1016/j.meegid.2009.09.017

Cited by 30 publications

(25 citation statements)

References 60 publications

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“…We focused on two issues in our analysis: (1) The involvement or not of ER stress-mediated apoptosis; and (2) whether the caspase-12 fragment plays any role in this phenomenon. Caspase-12 itself is an ER stress-specific protease and is expressed in about 10% of Caucasians (Pennington et al 2009). The precise pro-apoptotic functions of caspase-12 protein or its active fragment, however, remain unclear.…”

Section: Discussionsupporting

confidence: 89%

Appearance of Nuclear-sorted Caspase-12 Fragments in Cerebral Cortical and Hippocampal Neurons in Rats Damaged by Autologous Blood Clot Embolic Brain Infarctions

et al. 2011

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Following endoplasmic reticulum (ER) stress, cerebral infarctions have been reported to involve an apoptotic process, including the activation of the caspase cascade. To confirm whether fragmented caspase-12, which is activated by cleavage and is detectable during ER stress, is also involved in embolic cerebral infarctions in rats, we adopted an autologous blood clot model for the analysis of cerebral infarctions. We performed experiments in rats with brain infarctions, which are closely related to embolic cerebral infarctions. We utilized a homologous blood clot, i.e., natural materials, to form the infarct area. Our findings reveal that caspase-12 is fragmented when infarct areas form in cerebral cortical neurons. Interestingly, we observed that these fragments translocated to the nuclei of not only cerebral cortical neurons but hippocampal neurons. We further found that glucose-regulated protein 78 (GRP78), a marker of ER stress, is up-regulated in both cerebral cortical and hippocampal neurons during cerebral infarction. This result suggests that the fragmentation of caspase-12 and the subsequent nuclear translocation of these fragments are involved in the brain infarction process in rats.

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Section: Discussionsupporting

confidence: 89%

Appearance of Nuclear-sorted Caspase-12 Fragments in Cerebral Cortical and Hippocampal Neurons in Rats Damaged by Autologous Blood Clot Embolic Brain Infarctions

et al. 2011

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“…As reviewed by Pennington and colleagues [31] and Chapman and Hill [13] the high burden of infectious diseases in tropical Africa and the pressure to survive such life-threatening illnesses likely led to selection for those with more robust innate immune responses. It is possible that an exuberant innate immune response, in the form of robust inflammation, while being beneficial for resisting and surviving infectious diseases, may play a negative role in malignant transformation and cancer risk in later life [32–34].…”

Section: Discussionmentioning

confidence: 99%

Innate Immunity Pathways and Breast Cancer Risk in African American and European-American Women in the Women’s Circle of Health Study (WCHS)

et al. 2013

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African American (AA) women are more likely than European American (EA) women to be diagnosed with early, aggressive breast cancer. Possible differences in innate immune pathways (e.g., inflammatory responses) have received little attention as potential mechanisms underlying this disparity. We evaluated distributions of selected genetic variants in innate immune pathways in AA and EA women, and examined their associations with breast cancer risk within the Women’s Circle of Health Study (WCHS). In stage I of the study (864 AA and 650 EA women) we found that genotype frequencies for 35 of 42 tested SNPs (18 candidate genes) differed between AAs and EAs (corroborated by ancestry informative markers). Among premenopausal AA women, comparing variant allele carriers to non-carriers, reduced breast cancer risk was associated with CXCL5-rs425535 (OR=0.61, P=0.02), while among EA women, there were associations with TNFA-rs1799724 (OR =2.31, P =0.002) and CRP-rs1205 (OR=0.54, P=0.01). For postmenopausal women, IL1B-rs1143627 (OR=1.80, P=0.02) and IL1B-rs16944 (OR=1.85, P =0.02) were associated with risk among EA women, with significant associations for TNFA-rs1799724 limited to estrogen receptor (ER) positive cancers (OR=2.0, P =0.001). However, none of the SNPs retained significance after Bonferroni adjustment for multiple testing at the level of P0.0012 (0.05/42) except for TNFA-rs1799724 in ER positive cancers. In a stage II validation (1,365 AA and 1,307 EA women), we extended evaluations for four SNPs (CCL2-rs4586, CRP-rs1205, CXCL5-rs425535, and IL1RN-rs4251961), which yielded similar results. In summary, distributions of variants in genes involved in innate immune pathways were found to differ between AA and EA populations, and showed differential associations with breast cancer according to menopausal or ER status. These results suggest that immune adaptations suited to ancestral environments may differentially influence breast cancer risk among EA and AA women.

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“…In this complex stage, and on a wider scale, the human geographical dimension seems to play a consistent role. It has been observed that tropical Africans are specialized at fighting parasites with low virulence and extended life spans, while Europeans and perhaps Asians are better adapted to high virulence pathogens (75), suggesting that evolved responses to diverse pathogen loads among geographic groups may contribute to higher frequencies of inflammatory diseases in contemporary communities.…”

Section: Host–pathogen Interaction and The Evolutionary Selfmentioning

confidence: 99%

Towards a Liquid Self: How Time, Geography, and Life Experiences Reshape the Biological Identity

et al. 2014

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The conceptualization of immunological self is amongst the most important theories of modern biology, representing a sort of theoretical guideline for experimental immunologists, in order to understand how host constituents are ignored by the immune system (IS). A consistent advancement in this field has been represented by the danger/damage theory and its subsequent refinements, which at present represents the most comprehensive conceptualization of immunological self. Here, we present the new hypothesis of “liquid self,” which integrates and extends the danger/damage theory. The main novelty of the liquid self hypothesis lies in the full integration of the immune response mechanisms into the host body’s ecosystems, i.e., in adding the temporal, as well as the geographical/evolutionary and environmental, dimensions, which we suggested to call “immunological biography.” Our hypothesis takes into account the important biological changes occurring with time (age) in the IS (including immunosenescence and inflammaging), as well as changes in the organismal context related to nutrition, lifestyle, and geography (populations). We argue that such temporal and geographical dimensions impinge upon, and continuously reshape, the antigenicity of physical entities (molecules, cells, bacteria, viruses), making them switching between “self” and “non-self” states in a dynamical, “liquid” fashion. Particular attention is devoted to oral tolerance and gut microbiota, as well as to a new potential source of unexpected self epitopes produced by proteasome splicing. Finally, our framework allows the set up of a variety of testable predictions, the most straightforward suggesting that the immune responses to defined molecules representing potentials antigens will be quantitatively and qualitatively quite different according to the immuno-biographical background of the host.

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Group differences in proneness to inflammation

Cited by 30 publications

References 60 publications

Appearance of Nuclear-sorted Caspase-12 Fragments in Cerebral Cortical and Hippocampal Neurons in Rats Damaged by Autologous Blood Clot Embolic Brain Infarctions

Appearance of Nuclear-sorted Caspase-12 Fragments in Cerebral Cortical and Hippocampal Neurons in Rats Damaged by Autologous Blood Clot Embolic Brain Infarctions

Innate Immunity Pathways and Breast Cancer Risk in African American and European-American Women in the Women’s Circle of Health Study (WCHS)

Towards a Liquid Self: How Time, Geography, and Life Experiences Reshape the Biological Identity

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