Sex-specific regulation of immune responses by PPARs

Park, Hong Jai; Choi, Je-Min

doi:10.1038/emm.2017.102

Cited by 59 publications

(42 citation statements)

References 97 publications

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“…In addition, TLR3-TLR9 are implicated in EAE, which is also cell-mediated (Evangelista, et al, 2016). Additionally, peroxisome-proliferator activated receptor (PPAR) expression and activity in effector T cells, particularly in AD, is up-regulated by testosterone and down-regulated by oestrogens (Park and Choi, 2017), which is also consistent with the mechanism proposed here.…”

Section: Act Explains How Sex Alters Ad Risk and Why Some Ad Are Malesupporting

confidence: 84%

“…In male-dominant AD, ACT predicts that different sets of TLR will be activated that involve testosterone stimulation of their activity. Testosterone specifically enhances TLR 6 expression and function (Park and Choi, 2017;Al-Quraishy, et al, 2014). Thus, synergisms involving TLR6 (e.g., TLR 6 with 2) (see above and FIGURE X) should produce hyperinflammatory conditions that could support AD preferentially in males.…”

Section: Act Explains How Sex Alters Ad Risk and Why Some Ad Are Malementioning

confidence: 99%

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<strong>A General Theory of Autoimmune Disease Causation: Integrating Innate and Adaptive Immunity, Altered Antigen Processing, Sex and Genetic Predispositions, and Microbiome Effects</strong>

Root‐Bernstein¹

2019

Preprint

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Current theories of autoimmunity are diverse, sometimes contradictory, and suffer from incompleteness. Although substantial evidence exists that adaptive and innate immunity, sex, genetic predisposition, and the microbiome all play essential roles in autoimmune disease etiologies and pathogenesis, and that antigen processing is altered during disease induction, no existing theory integrates all of these factors through a single, coherent mechanism. In an attempt to focus the field on the need to elucidate such an integrative mechanism, I propose one possibility here that, if nothing else, helps to identify the nature of the problems that need to be addressed. My theory is that autoimmune diseases are induced by normal immunological responses to unique pairs of complementary antigens, at least one of which is a molecular mimic of a host target.  Each antigen in the complementary pair induces a complementary immune response (T or B cell); although each immune response is idiotypic in origin, the antigenic complementarity results in what appears to be an idiotype-anti-idiotype relationship between the responses. Additionally, because of the antigenic complementarity, each immune response mimics one of antigens, abrogating the distinction between self and non-self. If at least one of the antigens mimics a host antigen, then the resulting immunological civil war spreads to a host tissue. Complementary antigens also alter antigen processing so that antigens that would normally be proteolytically digested are presented by the major histocompatibility complex (MHC) to T and B cell receptors inducing a cross-reactive immune response. The resulting civil war is supported by the innate immune system due to the complementarity of the initiating antigens.. Complementary antigens stimulate synergistic toll-like receptors (TLR) and/or nucleotide-binding oligomerization receptors (NOD) resulting in up-regulation of cytokine production and further stimulation of the adaptive immune response. Because the immune responses (e.g., antibodies) mimic the initiating antigens, this synergistic activation of innate immunity becomes chronic. Additionally, TLR and NOD function are highly sensitive to sex hormones, some becoming up-regulated and some down-regulated in the presence of either testosterone or estrogens. This sensitivity explains how sex modifies susceptibility to autoimmune diseases. Genetic mutations in TLR, NOD and MHC further alter antigen presentation and the degree to which antigens stimulate an immune response explaining how genetics also modifies susceptibility. Finally, sex hormones also alter the host microbiome, which in turn modulates autoimmune disease risk by shaping the immunological nature of self and by mediating susceptibility to microbial infection.  Moreover, it appears that the microbiome camouflages itself from the immune system by mimicking the host antigenic repertoire; the mimicry between the antigens of the microbiome and the host results in selective attacks on microbiome constituents concomitant with any autoimmune attack on host tissues. This antigenic complementarity theory thereby integrates all major elements known to affect, or be affected by, autoimmune diseases and provides a set of testable implications.

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Section: Act Explains How Sex Alters Ad Risk and Why Some Ad Are Malesupporting

confidence: 84%

Section: Act Explains How Sex Alters Ad Risk and Why Some Ad Are Malementioning

confidence: 99%

<strong>A General Theory of Autoimmune Disease Causation: Integrating Innate and Adaptive Immunity, Altered Antigen Processing, Sex and Genetic Predispositions, and Microbiome Effects</strong>

Root‐Bernstein¹

2019

Preprint

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“…Moreover, larger epidemiologic studies 26 have shown that NA occurs more commonly in men (ratio 2: 1), and also in a recent French study, 22 5 of 6 HEV-NA cases were men. The reason(s) why HEV-associated NA is more common in men is unclear, but sex hormones are known to influence innate 33 and adaptive 34,35 immune response during viral infection. The immune response to virus is regulated by interferons (IFNs), and IFN treatment can induce bilateral NA.…”

Section: Discussionmentioning

confidence: 99%

Neurologic complications of acute hepatitis E virus infection

Ripellino

Pasi

Melli

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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ObjectiveTo assess the prevalence and clinical features of neurologic involvement in patients with acute hepatitis E virus (HEV) infection in Southern Switzerland.MethodsAmong 1,940 consecutive patients investigated for acute hepatitis E, we identified 141 cases of acute of HEV infection (anti-HEV immunoglobulin M and immunoglobulin G both reactive and/or HEV RNA positive) between June 2014 and September 2017. Neurologic cases were followed up for 6 months. We compared patients with and without neurologic symptoms.ResultsNeurologic symptoms occurred in 43 acute HEV cases (30.4%) and consisted of neuralgic amyotrophy (NA, n = 15, 10.6%) and myalgia (n = 28, 19.8%). All NA cases were immunocompetent. Men had higher odds (OR = 5.2, CI 1.12–24.0, p = 0.03) of developing NA after infection with HEV, and in 3 couples simultaneously infected with HEV, only men developed NA. Bilateral involvement of NA was predominant (2:1) and occurred only in men. Seven NA cases were viremic (all genotype 3), but HEV was undetectable in their CSF. In the acute phase of NA, 9 patients were treated with intravenous immunoglobulin and 4 with prednisone, reporting no side effects and improvement in pain and strength. Myalgia occurred both without (n = 16) or with (n = 12) concomitant elevated serum creatinine kinase. Seven cases with myalgia in the shoulder girdle did not have muscle weakness (“forme fruste” of NA).ConclusionsNeurologic symptoms occurred in one-third of acute HEV infections and consisted of NA and myalgia. NA seems to occur more frequently in men infected by HEV and has a predominant (but not exclusive) bilateral involvement.

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“…In general, once a viral infection is established, the activation, by the Antigen Presenting Cells (APCs), of adaptive immune responses and of B cells, with subsequent rise of the antibodies specific for viral antigens, in most cases is greater in female animals and humans compared to males ( 10 ). In addition, females have higher number of CD4 + T cells than males, that induces a greater number of T cells activated by viral antigens engagement of the T cell receptor ( 9 – 13 ); moreover, stronger cytotoxic T cell activity along with overexpression of antiviral and pro-inflammatory genes, many of which have estrogen response elements in their promoters, have been reported in women ( 14 ).…”

Section: Sex Disparity In Immune Responses To Viral Infectionsmentioning

confidence: 99%

Sex-Dependent Outcome of Hepatitis B and C Viruses Infections: Synergy of Sex Hormones and Immune Responses?

2018

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Hepatitis B virus (HBV) and hepatitis C virus (HCV) are hepatotropic viruses that differ in their genomic content, life cycle and molecular prognosis. HBV and HCV establish chronic lifespan infections that can evolve to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). This malignant liver cancer affects more commonly male patients than females, with a male-to-female incidence ratio of 2:1 up to 7:1. Sex significantly contributes to shape the immune responses, contributing to differences in the pathogenesis of infectious diseases, in males and females patients. Females usually develop more intense innate, humoral and cellular immune responses to viral infections and to vaccination compared to male subjects. Sex hormones, in turn, differentially affect the immune responses to viruses, by specific binding to the hormone receptors expressed on the immune cells. In general, estrogens have immune-stimulating effect, while androgens are immune-suppressing. However, sex hormones, such as androgen, can also directly interact with HBV genome integrated into the cell nucleus and activate transcription of HBV oncoproteins. On the other side, estradiol and estrogen receptors protect liver cells from inflammatory damage, apoptosis and oxidative stress, which contribute to fibrosis and malignant transformation preceding HCC. In HCV-associated cirrhosis and HCC the decreased expression of estrogen receptor alfa (ERα) in male patients may explain the worse outcome of HCV infection in men than in women. The synergistic action of male and female sex hormones and of immune responses, together with viral factors contribute to the mechanism of sex/gender disparity in the outcome and progression of hepatitis viruses infection.

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Sex-specific regulation of immune responses by PPARs

Cited by 59 publications

References 97 publications

<strong>A General Theory of Autoimmune Disease Causation: Integrating Innate and Adaptive Immunity, Altered Antigen Processing, Sex and Genetic Predispositions, and Microbiome Effects</strong>

<strong>A General Theory of Autoimmune Disease Causation: Integrating Innate and Adaptive Immunity, Altered Antigen Processing, Sex and Genetic Predispositions, and Microbiome Effects</strong>

Neurologic complications of acute hepatitis E virus infection

Sex-Dependent Outcome of Hepatitis B and C Viruses Infections: Synergy of Sex Hormones and Immune Responses?

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