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HLA Testing

HLA testing is commonly used to identify tissue match between a donor and a recipient, and for identifying certain disease conditions. To understand this better, it is important to delve a little into how our immune system is built.

The immune system is the body’s primary defence mechanism against falling sick. But, how does the body differentiate between which cells are ‘good’ and which are potentially harmful, such as the viral or bacterial or cancer cells?


Every cell in the body displays a specific set of identifying markers, sort of like fingerprints. Using these fingerprints the body’s defense cells recognize which cells are “safe” or “unsafe. The immune system then attacks and destroys the “unsafe” cells. Every individual carries their own signature of protein markers or “fingerprints” that are coded by a set of genes called the Major Histocompatibility Complex (MHC)  or the Human Leukocyte Antigen (HLA).

The HLA, therefore, is a complex of genes that give instructions to a set of proteins to be displayed on cells, but the term is also used to refer to the proteins themselves. This system is used by the body to determine which set of cells are native, hence, “safe” and which ones are foreign/unsafe.


The Major Histocompatibility Complex:

The human major histocompatibility complex HLA is present in chromosome 6 and is one of the most polymorphic genetic system in humans. The role of  the HLA class I and class II molecules is to ‘display’ or present antigens. Though this system is known for its relevance in transplantation biology, the main role of this complex is in regulating the immune system.  

Organization of the HLA system

The complex spans approximately 3,600 kilobases of DNA and is divided into three regions.

Class I region– This region contains the HLA-A, HLA-B, and HLA-C genes which code for the heavy chains of the class I molecule.

Class II region– This region consists subregions that have A and B genes, coding for α and β chains, respectively.

Class III region–  This region does not code for HLA molecules, but contains genes for the components of complement system.

Evolution of the Polymorphism in the HLA genes:

The immune system of the body has the herculean task of identifying potentially harmful cells and destroying them before they cause considerable harm to the body. This system has been constantly evolving to cater to the ever evolving environmental components which enter the individual through multiple means. This adaptation occurs through constant genetic recombination, like in the case of antibody formation.

Antigens are ‘threats’ to the body, like viruses, bacteria or other potentially harmful cells, such as cancer cells, which could affect the health of the body. Antibodies are the body’s defense that are secreted to fight against the antigens. Viruses, bacteria and other antigens constantly evolve to evade the attack by the host’s immune system. The HLA molecules that are associated with presenting the antigens on the surfaces of cells, have adapted to counteract the evolving antigen invasion. There is extensive duplication of genes, with functions that are redundant but in which there are small differences. The HLA molecules are largely conserved in areas of the protein that interact with the body’s T cell receptors and their co-receptors. However, there are extensive polymorphisms in areas associated with binding with antigens, this helps in keeping up with the constantly evolving antigens.

Studies have shown that there has been an exponential increase in the number of HLA polymorphisms during the last decade.

HLA haplotypes

HLA genes are linked very closely, which means that the entire MHC is inherited as an HLA haplotype, from each parent. The following about the segregation of HLA haplotypes which occurs within a family has been determined from family HLA studies .

Siblings have:

  • 25% chance of being genotypically HLA identical
  • 50% chance of sharing one haplotype (HLA haploidentical)
  • 25% chance sharing no HLA haplotypes.

HLA and association with disease

There are certain diseases, especially autoimmune diseases, that are associated with the HLA system. One of the most significant among them is the celiac disease. Other autoimmune conditions for which HLA genes have been associated are rheumatoid arthritis, systemic lupus erythematosus, Sjogren’s syndrome and type 1 diabetes mellitus.

Celiac Disease: This is an autoimmune disorder that occurs in the small intestine due to the presence of gluten proteins in individuals who carry certain variants of the HLA genes. The frequency of this condition varies from one geographical region to another. Initially it was believed that Europeans were the only ones affected with this condition. However, large scale studies conducted has shown that this disease is present in all parts of the world.  

In India, a study conducted on 23,331 adults showed that the presence of celiac autoantibodies was 1.23% in North, 0.87% in North Eastern and 0.10% in South Indian population. The study also found that the population prevalence of genes associated with celiac disease, HLA-DQ2 and/or -DQ8 expression was 38.1% in northern, 31.4% in northeastern, and 36.4% in southern India. The difference in the prevalence of this condition between north and south could be due to differences in dietary patterns. Moreover, individuals develop gluten intolerance or sensitivity without ever developing celiac disease. Nearly 95% of individuals who suffer from celiac disease have the DQ 2 or the DQ8 polymorphism.

What is HLA testing used for?

HLA testing is primarily used for these two key functions

  1. Donor tissue matching: This test involves identifying the HLA alleles of the recipient  and matching that with the donor to see if there is a match, to lower the risk of rejection
  2. Gene testing for autoimmune conditions: Gene HLA testing is carried out to identify the type of HLA haplotype carried and the risk of diseases.

Xcode Life carries out HLA testing to identify the risk for gluten intolerance- celiac disease, as a part of the nutrition report.


What is the benefit of carrying out a HLA testing for gluten intolerance?

The genetic HLA testing helps in identifying individuals who carry the genes associated with the increased risk of gluten intolerance. The most significant of these are the HLA DQ2 and HLA DQ8 polymorphisms.

There are two important reasons for carrying out HLA testing?

  1. To rule out gluten intolerance: The absence of any gene variants associated with celiac disease ‘rules out’ the presence of this condition. The individual can never ‘develop’ this condition even later.
  2. To identify if gluten free diet is warranted: There has been a significant increase in the number of people who are on a gluten free diet but who have not been tested for gluten intolerance. Since such individuals may not want an invasive procedure like a biopsy to confirm the presence of gluten intolerance, a genetic HLA testing could help in identifying the condition.


What does a positive HLA testing for gluten intolerance indicate?

A positive HLA test is not diagnostic of the presence of the condition, but is indicative of an increased likelihood of the condition. People who test positive should watch out for symptoms and should undergo antibody testing to detect the condition. It places the individuals in an ‘at risk’ group, requiring repeated monitoring.


How is genetic HLA testing different from antibody HLA testing?

Most individuals are familiar with antibody testing like transglutaminase test or the antiendomysial antibody test. These tests identify the presence of antibodies to gluten present at that point of time.

A genetic HLA testing will identify ‘at risk’ individuals irrespective of their current dietary patterns. One does not need to be consuming gluten to take this test.

Who should take up HLA testing for gluten intolerance?

  • People who suffer from abdominal discomfort and who suspect gluten intolerance can take up this test.
  • Children of parents with gluten intolerance can take up this test. Not all children of parents with the condition inherit the polymorphisms and develop the condition. Therefore screening children will help in identifying children who require repeated monitoring and children for whom gluten intolerance can be ruled out.
  • People who are currently on a gluten free diet but who have not been tested for the condition, and for whom a biopsy is not currently an option.

The Xcode nutrition report includes the risk for gluten intolerance, apart from response to various macro and micronutrients and food sensitivities.




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