HLA and non-HLA genes and familial predisposition to autoimmune diseases in families with a child affected by type 1 diabetes

Parkkola, Anna; Laine, Antti‐Pekka; Karhunen, Markku; Härkönen, Taina; Ryhänen, Samppa J.; Ilonen, Jorma; Knip, Mikael

doi:10.1371/journal.pone.0188402

Cited by 17 publications

(13 citation statements)

References 56 publications

(38 reference statements)

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“…It is clearly documented that genetic predisposition plays an important role in the development of both diabetes type 1 and type 2 [4,5]. Advanced age is another non-modifiable risk factor for diabetes manifestation.…”

Section: Non-modifiable Risk Factorsmentioning

confidence: 99%

Diabetes care in figures: current pitfalls and future scenario

2018

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Diabetes mellitus (DM) epidemic-on a global scale-is a major and snowballing threat to public health, healthcare systems and economy, due to the cascade of pathologies triggered in a long-term manner after the DM manifestation. There are remarkable differences in the geographic disease spread and acceleration of an increasing DM prevalence recorded. Specifically, the highest initial prevalence of DM was recorded in the Eastern-Mediterranean region in 1980 followed by the highest acceleration of the epidemic characterised by 0.23% of an annual increase resulted in 2.3 times higher prevalence in the year 2014. In contrast, while the European region in 1980 demonstrated the second highest prevalence, the DM epidemic developments were kept much better under control compared to all other regions in the world. Although both non-modifiable and modifiable risk factors play a role in DM predisposition, cross-sectional investigations recently conducted amongst elderly individuals demonstrate that ageing as a non-modifiable risk factor is directly linked to unhealthy lifestyle as a well-acknowledged modifiable risk factor which, in turn, may strongly promote ageing process related to DM even in young populations. Consequently, specifically modifiable risk factors should receive a particular attention in the context of currently observed DM epidemic prognosed to expand significantly over 600 million of diabetes-diseased people by the year 2045. The article analyses demographic profiles of DM patient cohorts as well as the economic component of the DM-related crisis and provides prognosis for future scenarios on a global scale. The innovative approach by predictive diagnostics, targeted prevention and treatments tailored to the person in a suboptimal health condition (before clinical onset of the disease), as the medicine of the future is the most prominent option to reverse currently persisting disastrous trends in diabetes care. The key role of biomedical sciences in the future developments of diabetes care is discussed.

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Section: Non-modifiable Risk Factorsmentioning

confidence: 99%

Diabetes care in figures: current pitfalls and future scenario

2018

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“…Several studies have observed a shared genetic pathway for non-HLA genes that may predispose to autoimmune diseases in children and adults (39)(40)(41)(42)(43). Although relevant to its occurrence, non-HLA loci do not appear to favor progression of the disease toward severe complications such as refractory celiac disease type II (RCD II), a condition that frequently evolves to intestinal lymphoma (44).…”

Section: Genetic Variants Of Non-hla Loci Associated With Celiac Diseasementioning

confidence: 99%

Beyond the HLA Genes in Gluten-Related Disorders

et al. 2020

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Most common food grains contain gluten proteins and can cause adverse medical conditions generally known as gluten-related disorders. Celiac disease is an immune-mediated enteropathy triggered by gluten in individuals carrying a specific genetic make-up. The presence of the human leukocyte antigens (HLA)-DQ2 and HLA-DQ8 haplotypes together with gluten intake is a necessary, although not sufficient, condition, to develop celiac disease. Fine mapping of the human genome has revealed numerous genetic variants important in the development of this disease. Most of the genetic variants are small nucleotide polymorphisms located within promoters and transcriptional enhancer sequences. Their importance is underlined by an increased risk in DQ2/DQ8 carriers who also have these non-HLA alleles. In addition, several immune-mediated diseases share susceptibility loci with celiac disease, shedding light on the reasons for co-occurrence between these diseases. Finally, most of the genes potentially involved in celiac disease by fine genetic mapping of non-HLA loci were confirmed in gene expression studies. In contrast to celiac disease, very little is known about the genetic make-up of non-celiac wheat sensitivity (NCWS), a clinically defined pathology that shares symptoms and gluten dependence with the celiac disease. We recently identified differentially expressed genes and miRNAs in the intestinal mucosa of these patients. Remarkably, the differentially expressed genes were long non-coding RNAs possibly involved in the regulation of cell functions. Thus, we can speculate that important aspects of these diseases depend on alteration of regulatory genetic circuits. Furthermore, our finding suggests that innate immune response is involved in the pathogenic mechanism of NCWS. This review is intended to convey the idea that in order to fully understand celiac disease and its relationship with other gluten-related disorders, it is worth learning more about non-HLA variants.

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“…Mutations in MHC/HLA would be likely to alter processing and presentation of antigens so that they induce host-cross-reactive immune responses. Similarly, genetic variants of immune regulatory proteins such as CD40, CD25, CD69, CTLA4, CCR3 and CCR5 are also known to increase susceptibility to various AD presumably by interfering with normal tolerance mechanisms (Tomer, 2010;Zagoriti, et al, 2013;Parkkola, et al, 2017). Genetic mutations in the innate immune system can also modify how sensitive the system is to any particular type of microbial antigen (Delgado-Vega, et al, 2010).…”

Section: Act and Genetic Predisposition To Autoimmune Diseasesmentioning

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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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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HLA and non-HLA genes and familial predisposition to autoimmune diseases in families with a child affected by type 1 diabetes

Cited by 17 publications

References 56 publications

Diabetes care in figures: current pitfalls and future scenario

Diabetes care in figures: current pitfalls and future scenario

Beyond the HLA Genes in Gluten-Related Disorders

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

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