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Biomarkers of Diabetes
Published in Awanish Kumar, Ashwini Kumar, Diabetes, 2020
Before moving on to the serum biomarkers for T1DM, we must mention briefly the genetic markers. Mutation and variation in HLA genotypes are widely associated with the risk of progression of T1DM. This high risk is attributed due to the fact that the HLA genes are highly responsible for T-cell selection, antigen presentation and T-cell activation. Among the HLA alleles, HLA DR and HLA DQ class II loci are most responsible for the T1DM risk. Among these, specifically, HLA DRB1*03, HLA DRB1*04 and HLA DQB1*0302 (HLA DR3/4 DQ8) impart the highest risk in the development and progression of T1DM. Apart from the HLA genotypes, two other genes, INS (the pro-insulin gene) and PTPN22 (protein tyrosine phosphatase N22), also significantly increase the risk of development of T1DM. A VNTR variant of INS, INS VNTR I, is shown to be responsible for increased T1DM risk while an increase in phosphatase activity of PTP is seen in T1DM patients [4].
Celiac disease
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Like most chronic inflammatory diseases, celiac disease has a multifactorial etiology, as both genes and environmental factors contribute to disease pathogenesis. In this regard, exclusion of gluten from the diet results in resolution of the disease, and the absence of the HLA predisposing genes is associated with reduced likelihood of developing celiac disease (99% of patients have the HLA-DQ2 or HLA-DQ8 haplotypes, see later). A high degree of familial clustering (10% of first-degree relatives affected compared to a population prevalence of about 1%) and a large difference in the concordance rate between monozygotic and dizygotic twins (75% versus 10%) suggest a genetic contribution. Both HLA genes and non-HLA genes are implicated in the disease. Most people who express HLA risk genes do not develop the disease, and the concordance rate among HLA-identical dizygotic twins who share their HLA genes in addition to half of their non-HLA genes is much lower than that of monozygotic twins.
Immunopathology
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
The most clearly demonstrated genetic associations of autoimmune diseases are with the HLA complex (see Chapter 8). This would seem to be expected since these genes play such an important role in T cell development and their antigen responses. Thus, autoimmunity-related HLA genes may influence thymic selection such that autoreactive clones are positively selected, or fail to be deleted. Some HLA molecules may present foreign peptides which closely resemble self components, or they may actually present “pathogenic” self epitopes. One must keep in mind that these genetic associations are far from absolute. The presence of the gene is simply one additional factor which increases predisposition to disease.
Outcomes of thymoglobulin versus basiliximab induction therapies in living donor kidney transplant recipients with mild to moderate immunological risk – a retrospective analysis of UNOS database
Published in Annals of Medicine, 2023
Hatem Ali, Mahmoud Mohammed, Tibor Fülöp, Shafi Malik
HLA matching has a vital effect on the outcome of kidney transplantation [17]. While total HLA mismatching represents an important prognostic factor [16,17], HLA class II, especially HLA-DR mismatching has a greater impact on outcomes after kidney transplantation [2]. This is due to the high polymorphism in HLA Class II antigens. HLA class II antigens are present both in B-cells and antigen-presenting cells (APCs), which play a crucial role in the development of acute cell-mediated and antibody-mediated rejection. These antigen-presenting cells engulf process antigens and stimulate CD4 T-cells. The high polymorphism characteristic of Class II HLA antigens present on the APCs plays a pivotal role in identifying a large repertoire of foreign antigens. On the other hand, this high polymorphism acts as a barrier against successful transplantation, identifying allograft antigens as foreign antigens and stimulating rejection. Data from large registry studies have shown an approximately 7–13% higher risk of graft failure associated with one HLA mismatch and about 64–74% higher risk associated with six HLA mismatches [2, 18] with HLA-DR matching having a much greater effect on the number of rejection episodes and poor long-term survival [19, 20].
The impact of the HLA DQB1 gene and amino acids on the development of narcolepsy
Published in International Journal of Neuroscience, 2022
Leila Kachooei-Mohaghegh-yaghoobi, Fatemeh Rezaei-Rad, Khosro Sadeghniiat-Haghighi, Mahdi Zamani
The human leukocyte antigen (HLA) complex is a group of related proteins which are encoded by the major histocompatibility complex (MHC) gene in humans. These genes are located on chromosome 6 and based on their specific function which are divided into three sub-regions of HLA class I, II and III. HLA class I and II code for glycoproteins which are involved in antigen processing and surface antigen presentation to cytotoxic and regulatory T lymphocytes, respectively. Specific components of HLA class II are encoded by HLA-DRB1, DQA1, and DQB1 genes that are linked to autoimmune diseases such as type I diabetes, rheumatoid arthritis and Graves’ disease [2–5]. HLA class II genes are generally expressed on the surface of antigen-presenting cells, including B cells, macrophages, dendritic cells, etc. The binding and presentation of processed antigens that are mediated by HLA proteins are critical to the development of tolerance in the thymus (by deletion of self-reactive T cells) and determination of an immune response in the periphery. Therefore it is not unexpected that vast majority of autoimmune diseases show associations with variants of HLA genes.
Systemic Immunosuppression in Cornea and Ocular Surface Disorders: A Ready Reckoner for Ophthalmologists
Published in Seminars in Ophthalmology, 2022
High risks grafts have traditionally been defined as those with two or more quadrants of deep vascularization or those with previous history of graft failure.135 In these patients, the prevention of rejection with HLA matching of the donor and the host has been found to have good outcomes.136 With respect to topical therapy, topical steroids are again the mainstay of therapy, with higher maintenance doses over the initial 1–2 years.129,130 This is usually combined with topical or oral calcineurin inhibitors. Topical cyclosporine A has not shown promising results in the prevention of graft rejection. One hypothesis suggested for the same has been decreased availability of the drug within the aqueous due to its lipophilic nature.137 This is over come with the oral use of the medication which has shown to reduce the risk of rejection especially with prolonged use for at least 12 months.62,138 Topical tacrolimus has had better results with efficacy similar to that of topical steroids.132,139 A combination of topical steroids and topical tacrolimus is recommended as a maintenance therapy in high risk grafts.139