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HLA DNA typing – Disease Association
By Miguel M Castro and Dante J Marciani
Created On
Monday, March 1, 2010
Last Modified On
Thursday, March 3, 2011
Last Modified By

HLA DNA typing – Disease Association

Miguel M Castro y Dante J Marciani

HLA or “human leukocyte antigen” system is the major histocompatibility complex (MHC) in humans, which includes several hundreds of genes located in a highly polymorphic region of chromosome 6 that encode for proteins critical for the immune system [1]. Historically, these proteins are called antigens because of their discovery as crucial factors in tissue rejection by the host, a critical matter in organ transplantations. Thus, typing of the HLAs from donor and recipient, allows matching those with the highest similarities between their HLA genes or alleles to minimize the chances of rejection; an application that is still the most important for HLA typing. In fact, the HLA profile defines the cells from an individual or “self”, distinguishing them from those from other individuals showing a different HLA profile, “non-self”. As indicated, HLAs play a critical role in the immune system, particularly in antigen presentation, the process by which macrophages and dendritic cells or antigen presenting cells, process antigens for recognition by T cells. The two main HLA groups involved in antigen presentation are the Class I and Class II antigens that have different immunological roles.

HLA Class I antigens (A, B and C) transport and present peptides produced by degradation of proteins inside the cell, i.e. endogenous antigens such as viral antigens, to CD8+ T cells (killer T cells) that seek and destroy only those cells that in addition to the HLA Class I, carry also foreign or not-self antigens (T cell immunity). Under normal conditions, these killer T cells recognize but do not destroy those cells with the right “self” tag, i.e. HLA-I, unless they also carry a non-self antigen. Yet, under pathological conditions, like in certain autoimmune conditions, killer T cells can destroy cells carrying self-antigens, causing damage to the body.

In contrast to HLA-Class I, the role of HLA Class II antigens (DRB1, DRB3,4,5, DQA1/DQB1, DPB1) is to present the peptides from processed proteins that are produced outside the cell, exogenous antigens derived from sources like bacteria and protozoa, to helper T-cells to stimulate their multiplication. These helper T cells then stimulate B-cells to produce antibodies against the foreign antigens (humoral immunity) [2].

Although HLA typing is largely use to match organ donors and recipients, advances in the biomedical field has allowed the typing techniques to become more accurate and yield more detail information. Studies using this new information have made obvious the fact that there are significant correlations between certain HLA types and specific diseases. Consequently, HLA typing is becoming a tool to screen susceptibility to certain autoimmune diseases, as a factor affecting the prognosis of certain autoimmune and infectious diseases. However, the association between HLA type and most infectious diseases is not very clear because of the multiplicity of factors that can affect their outcome. Nevertheless, in some cases such a relation is obvious, a situation that may be helpful in establishing either the resistance or susceptibility to certain infectious diseases and even a prognosis of the disease progression [3]. Another area in which HLA typing is becoming quite important is cancer, a class of diseases where HLAs can play a role in increasing susceptibility and resistance, as well as in tumor cells evading immune surveillance. Moreover, in some cases, the HLA type shows a good correlation with the prognosis of the disease upon treatment. Here, we would discuss the different applications of HLA DNA-typing to autoimmune, infectious diseases and cancer.

Autoimmune diseases

As previously indicated, the immune system under normal conditions is usually tolerant to cells carrying “self” HLAs, i.e. it does not mount an immune response against them. Yet, in many cases, there is a mild low level of autoimmunity that presumably allows immune surveillance by the immune system and the destruction of newly formed cancer cells. Although apparently there are several genes suspected to be involved in autoimmunity, there is strong evidence that certain inherited HLAs are involved in certain specific autoimmune diseases. Because of their important role in the presentation of processed antigens to T cells, HLAs are in a unique position to modify the immune response and cause autoimmunity. HLAs can determine which antigenic peptides are bound for presentation to the immune system, thus it can present “self” peptides auto reactive T cells. In other cases, certain HLAs may bind peptides from infectious agents that share some similarities to the self-antigens to generate an immune response against self-antigens; this molecular mimicry often leads to autoimmunity. In fact, several HLAs, like HLA-B27, are associated with various autoimmune inflammatory diseases. Some of these autoimmune diseases, their association to specific HLAs, and the relative risk of acquiring the disease as a function of specific HLAs are briefly discuss here.

Rheumatoid Arthritis. An inflammatory disease that is the result of a complex immune cascade and that its susceptibility is dependent on the presence of HLA-DR4 and HLA-DRB1 [4]. Presence of these HLA types increases the risk factor of contracting the disease 7-fold when compared to that population not carrying these HLA genes. In Peruvian mestizo patients the HLA allele DRB1*1402 is associated with a significant risk of contracting the disease.

Post-infectious Arthritis. An inflammatory condition of the joints, triggered by gastrointestinal or genitourinary bacterial infections or by a viral infection. Although it is assume that the synovial fluid is sterile, studies using PCR had detected bacterial DNA in the fluid. It has been found that individuals that suffer of this disease carry the gene for HLA-B27 and that the risk factor increases 10 to 20-fold [5]. Diagnosis is usually made by examining the synovial fluid for the presence of pathogenic antigens or DNA. However¸ detection of the HLA-B27 gene should be an effective confirmatory test.

Type I Diabetes. A disease strongly linked to HLA genes, however, the relative importance of the different HLA genes involve is quite complex and changing with new discoveries in the area. Moreover, in addition to the HLA genes there are other unrelated genes that play a role in the susceptibility to contract the disease. The HLA-DR3 and DR4 genes have been identified as playing important roles and that the presence of any of these two genes increases the risk of contracting the disease 5-6-fold, while the presence of both genes increases the risk factor to 15 [6]. Yet, new research indicates that some HLA-DQ genes play a role in susceptibility to the disease that is even higher than that of the DR genes.

Autoimmune Hepatitis. An inflammation of the liver due to unknown causes that raises the possibility that the chronic hepatitis observed in many patients may be in many cases due to an autoimmune reaction. The incidence of autoimmune hepatitis in South America although not well established it is apparently significant. Like other autoimmune diseases, there are genetic factors that affect its occurrence, e.g. HLAs; however, different ethnic groups have different susceptibility alleles. For instance, in South America is HLA DRB1*1301 while in Europe is HLA DR3. These HLAs have significant differences in their sequences within the antigen binding grove of the HLA DR molecule [7]. This fact strongly suggests that perhaps an unidentified indigenous etiologic agent must be the cause of autoimmune hepatitis in

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