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Major Histocompatibility Complex and Autoimmune Disease
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Ursula Holzer, Gerald T. Nepom
For inflammatory bowel disease, such as Crohn’s disease and ulcerative colitis, a genetic predisposition is strongly supposed.45 The genes in the HLA region are candidate genes contributing to susceptibility for these diseases as they encode functionally relevant gene products in the gut epithelium and they colocalize to a linkage region on chromosome 6.46,47 The association with HLA-DRB1*0103 and extensive ulcerative colitis has been widely replicated.46,48,49 For Crohn’s disease, an association with DR7, DRB3*0301 and DQ4 were found.49 Nevertheless, the contribution of HLA-DQ genes is less clear-cut in these diseases and the association of HLA-DR molecules in the pathogenesis of ulcerative colitis may be threefold larger compared with Crohn’s disease.49 Non-HLA genes, such as NOD2 (a family of cytosolic proteins that regulate the host response to pathogens), are known to be contributory in this disease, as are environmental agents and bacterial gut flora, so the exact role for HLA genes in disease initiation or progression is not clear.
Cellular Biology in Tissue Engineering
Published in Joseph W. Freeman, Debabrata Banerjee, Building Tissues, 2018
Joseph W. Freeman, Debabrata Banerjee
Histocompatibility antigens responsible for the most vigorous allograft rejection reactions are located on the major histocompatibility complex (MHC). They are inherited as haplotypes or two half sets (one from each parent). This makes a person half identical to each of his or her parents with respect to the MHC complex. Every person expresses 6 MHC1 alleles (HLA-A, HLA-B, HLA-C—one from each parent) and at least 6 MHC2 alleles (HLA-DQ, HLA-DP, HLA-DR—one from each parent). The MHC molecules are divided into two classes. The class I molecules are normally expressed on all nucleated cells, whereas the class II molecules are expressed only on the professional antigen-presenting cells (APCs), such as dendritic cells, activated macrophages, and B cells. The physiological function of the MHC molecules is to present antigenic peptides to T cells. The class I molecules are responsible for presenting antigenic peptides from within the cell (e.g., antigens from the intracellular viruses, tumor antigens, self-antigens) to CD8 T cells. The class II molecules present extracellular antigens such as extracellular bacteria to CD4 T cells. The activation of T cells is dependent on two essential signals. In addition to the bond formed by the MHC and the TCR, there is also the need for a secondary co-stimulatory response. This secondary response occurs when a bond is formed between the molecule B7 and CD28 on APCs and Helper T cells, respectively.
Head Transplantation: The Immune System, Phantom Sensations, and the Integrated Mind
Published in The New Bioethics, 2018
In the vocabulary of immunology, the expressions ‘self’ and ‘non-self’ may be thrown about with such abandon that these expressions are easily used to conflate issues in the broader language of personhood. It is important, therefore, to remember that when these expressions are used in immunology they are concerned with molecular recognition. The immune system consists of a network of molecular and cellular systems that undertake the critical function of differentiating that which is described in immunological terms as ‘self’ from that which is ‘non-self’ and imposes a level of identity on cells and tissues that must be considered in any transplant operation. These systems are typically grouped under the general headings ‘innate immunity’ and ‘adaptive immunity’ and involve more than 1600 genes (Abbas et al. 2005). Underpinning the adaptive responses are protein complexes brought together under the general heading the ‘major histocompatibility complex’ (MHC), also referred to as ‘human leukocyte antigens’ (HLA) when specific human MHC proteins are being referenced. MHC antigens are grouped into a number of classes, which, in broad terms, might be said to share function, insofar as they may, for example, process proteins into small chunks that are then presented to the T-cell receptor (TcR) on T-cells (La Gruta et al. 2018). They do, however, differ structurally from each other and serve different specific tasks. One of these, MHC class I (MHC-I, of which HLA-A, HLA-B, and HLA-C are members), is normally present on all nucleated cells, and subclasses of this are expressed within the first three days of the life of a human embryo (Wang et al. 2009). The absence MHC-I expression on cells leaves them vulnerable to destruction through the action of the MHC-I-sensing ‘killer cell immunoglobulin-like receptor’ (KIR), present on subpopulations of immune cells known as Natural Killer (NK) cells and subsets of T-cells. An important exception to this is the red blood cell population. Red cells do not express MHC-I, instead escaping destruction by NK cells through the expression of another protein, CD47 (Wang et al. 2010). Alongside the MHC-I, the expression of MHC class II (MHC-II, comprising HLA-DP HLA-DQ and HLA-DR in humans) and minor histocompatibility antigens (MiHA) like the male-specific H-Y antigen. The result of this is that, by the 8-cell stage of the embryo, the embryo is immunologically reactive with respect to the mother and its continued development requires the induction of immunological tolerance within the womb to prevent fetal rejection and miscarriage (Fernandez et al. 1999; Larsen et al. 2013; Colucci 2017).