Autism and the Immune system – Special (Torres)

Autism Research and Treatment
Volume 2012 (2012), Article ID 959073, 13 pages
doi:10.1155/2012/959073Review Article

HLA Immune Function Genes in Autism

http://www.hindawi.com/journals/aurt/2012/959073/

Anthony R. Torres,1 Jonna B. Westover,1 and Allen J. Rosenspire2

1Center for Persons with Disabilities, Utah State University, 6804 Old Main Hill, Logan, UT 84322,  USA
2Department of Immunology and Microbiology, School of Medicine, Wayne State University, 221 Lande Building, Detroit, MI 48201,  USAReceived 10 October 2011; Accepted 11 November 2011Academic Editor: Judy Van de Water Copyright © 2012 Anthony R. Torres et al.

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The human leukocyte antigen (HLA)* genes on chromosome 6 are instrumental in many innate and adaptive immune responses. The HLA genes/haplotypes can also be involved in immune dysfunction and autoimmune diseases. It is now becoming apparent that many of the non-antigen-presenting HLA genes make significant contributions to autoimmune diseases.

Interestingly, it has been reported that autism subjects often have associations with HLA genes/haplotypes, suggesting an underlying dysregulation of the immune system mediated by HLA genes. Genetic studies have only succeeded in identifying autism-causing genes in a small number of subjects suggesting that the genome has not been adequately interrogated. Close examination of the HLA region in autism has been relatively ignored, largely due to extraordinary genetic complexity. It is our proposition that genetic polymorphisms in the HLA region, especially in the non-antigen-presenting regions, may be important in the etiology of autism in certain subjects.

Full study at link

Summary

There is mounting evidence that the immune system plays a role in the pathogenesis of ASD in certain individuals. This evidence comes from several research areas including an increase in proinflammatory cytokines in blood and brain, autoantibodies to numerous antigens, and HLA associations.

Autism HLA associations have been observed across the entire HLA region.

For example, in the class I region HLA-A2 has been associated with autism by at least two research groups [156, 157]. In the class II region several researchers have reported autism associations with the DRβ1*04 allele [93, 99, 100].

Strong associations also appear in the class III region where the C4B null allele has been associated with autism with relative risks of 4.3 [94] and 4.6 [97], and an odds ratio of 6.3 [103]. The HLA-associated risk is the highest for autism (19.8) when combining two ancestral haplotypes (44.1 and 62.1). Both of these haplotypes have HLA-A2 and DRβ1*0401 as well as other genetic similarities; however, these two alleles cannot account for all of the 19.8 risk. Compared to other genetic associations with autism, the HLA associations may be more important than realized, as they have the highest genetically associated risk, that we are aware of for autism. For example the MET gene, one of the most studied genetic regions in autism, has a relative risk of 2.27 [17].

It is our premise that some of the autism missing inheritance may be hidden in the HLA region, both in classical HLA alleles and nonclassical HLA genes, as seen in schizophrenia [31].

For example, the HLA class III region contains clusters of genes such as TNF-α, HSP70, C4A/C4B, and NF-κBIL1 that are seminal in cellular function and are also associated with numerous autoimmune diseases (Table 3).

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http://en.wikipedia.org/wiki/Human_leukocyte_antigen

The human leukocyte antigen (HLA) system is the name of the major histocompatibility complex (MHC) in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and has many other functions. The HLA genes are the human versions of the MHC genes that are found in most vertebrates (and thus are the most studied of the MHC genes). The proteins encoded by certain genes are also known as antigens, as a result of their historic discovery as factors in organ transplants. The major HLA antigens are essential elements for immune function. Different classes have different functions:

HLAs corresponding to MHC class I (A, B, and C) present peptides from inside the cell (including viral peptides if present). These peptides are produced from digested proteins that are broken down in the proteasomes. In general, the peptides are small polymers, about 9 amino acids in length. Foreign antigens attract killer T-cells (also called CD8 positive- or cytotoxic T-cells) that destroy cells.

HLAs corresponding to MHC class II (DP, DM, DOA, DOB, DQ, and DR) present antigens from outside of the cell to T-lymphocytes. These particular antigens stimulate the multiplication of T-helper cells, which in turn stimulate antibody-producing B-cells to produce antibodies to that specific antigen. Self-antigens are suppressed by suppressor T-cells.

HLAs corresponding to MHC class III encode components of the complement system.

HLAs have other roles. They are important in disease defense. They may be the cause of organ transplant rejections. They may protect against or fail to protect (if down regulated by an infection) against cancers.[1] They may mediate autoimmune disease (examples: type I diabetes, coeliac disease). HLA may also be related people’s perception of the odor of other people, and may be involved in mate selection, as at least one study found a lower than expected rate of HLA similarity between spouses in an isolated community.[2]

Aside from the genes encoding the 6 major antigen-presenting proteins, there are a large number of other genes, many involved in immune function, located on the HLA complex. Diversity of HLAs in the human population is one aspect of disease defense, and, as a result, the chance of two unrelated individuals with identical HLA molecules on all loci is very low. HLA genes have historically been identified as a result of the ability to successfully transplant organs between HLA-similar individuals.

Functions

In infectious disease

When a foreign pathogen enters the body, specific cells called antigen-presenting cells (APCs) engulf the pathogen through a process called phagocytosis. Proteins from the pathogen are digested into small pieces (peptides) and loaded onto HLA antigens (to be specific, MHC class II). They are then displayed by the antigen-presenting cells to T cells, which then produce a variety of effects to eliminate the pathogen.

Through a similar process, proteins (both native and foreign, such as the proteins of virus) produced inside most cells are displayed on HLAs (to be specific, MHC class I) on the cell surface. Infected cells can be recognized and destroyed by CD8+ T cells.

The image off to the side shows a piece of a poisonous bacterial protein (SEI peptide) bound within the binding cleft portion of the HLA-DR1 molecule. In the illustration far below, a different view, one can see an entire DQ with a bound peptide in a similar cleft, as viewed from the side. Disease-related peptides fit into these “slots” much like a hand fits into a glove. When bound, peptides are presented to T cells. T cells require presentation via MHC molecules to recognize foreign antigens — a requirement known as MHC restriction. These cells have receptors that are similar to B cell receptors, and each cell recognizes only a few class II-peptide combinations. Once a T cell recognizes a peptide within an MHC class II molecule, it can stimulate B-cells that also recognize the same molecule in their B cell receptors. Thus, T cells help B cells make antibodies to the same foreign antigens. Each HLA can bind many peptides, and each person has 3 HLA types and can have 4 isoforms of DP, 4 isoforms of DQ and 4 Isoforms of DR (2 of DRB1, and 2 of DRB3,DRB4, or DRB5) for a total of 12 isoforms. In such heterozygotes, it is difficult for disease-related proteins to escape detection.

In autoimmunity

HLA types are inherited, and some of them are connected with autoimmune disorders and other diseases. People with certain HLA antigens are more likely to develop certain autoimmune diseases, such as type I diabetes, ankylosing spondylitis, celiac disease, SLE (systemic lupus erythematosus), myasthenia gravis, inclusion body myositis, and Sjögren syndrome. HLA typing has led to some improvement and acceleration in the diagnosis of celiac disease and type 1 diabetes; however, for DQ2 typing to be useful, it requires either high-resolution B1*typing (resolving *02:01 from *02:02), DQA1*typing, or DR serotyping. Current serotyping can resolve, in one step, DQ8. HLA typing in autoimmunity is being increasingly used as a tool in diagnosis. In celiac disease, it is the only effective means of discriminating between first-degree relatives that are at risk from those that are not at risk, prior to the appearance of sometimes-irreversible symptoms such as allergies and secondary autoimmune disease.

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This entry was posted in Autism, Epigenetics, General, Genetics, Immune System, Inflammation, Neurology, Physiology, Schizophrenia, Treatment and tagged . Bookmark the permalink.

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