Friday, 6 September 2013

You said what is HLA?

Yesterday we were saying that MSers in Sardinia Italy have (HLA) DR4 compared to the usual (HLA) DR2 of Northern Europeans.  You asked what does this mean. 

Well this is a repost

Education: What is the HLA?

Leucocyte is a British word for white blood cell. A leukocyte is an American white blood cells  from Leukos (white in Greek) and Cyte = cell.

The HLA means the Human Leucocyte antigen (HLA) which is also known as the major histocompatilibilty complex (MHC). This region coded on chromosome 6 determines the individuality of each of us. 

This is very different between each individual because there are alot of different variants of the molecules that make up the MHC. 

These variants are learnt by the T cells that you produce so that it can recognise who you are and importantly who you aren't so that it can detect and fight infections.  

There are two main components these are MHC class I (HLA-A, HLA-B, HLA-C) and MHC class II (HLA-DR, HLA-DP, HLA-DQ). 

The class  I molecules are made up of a variable chain and an invariant molecule called beta 2 microglobulin. 

The class II molecules are made up of two chains an alpha and a beta chain. 

These meet to have a cleft or a groove between them and inside this cleft sits a peptide (amino acids strung together), which is what T cells recognise. They recognise linear sequences from the protein compared to the three-dimensional structure that antibodies,typically recognise.
There molecules have different functions related to their structure and how the peptides from the breakdown of proteins are loaded into the MHC molecules

The different molecules have differnt functions but the real biology is to detect pathogens (Viruses and bacteria) inside and outside of the cell.

Whilst peptides are loaded into MHC class I in the endoplasmic reticulum, which is the place where proteins are made, MHC class II cannot be loaded because they have a blocking molecule called the invariant chain. 

This is removed by a molecule called CLIP and then the class II can be loaded with peptide, but this occurs in an endosome in the cytoplasm away from the endpoplasmic reticulum.



There are alot of different variants of each class I and class II chains so you get one set of variants from mum and another from dad and when you can see how many different genetic variants of each molecule then you can see why it can be used for genetic fingerprinting because the full genetic code can and is very different between individuals. 2.9  to the power 17 is about 300 hundred million, trillion different combinations.  
 
We know that the more important genetic variants linking to susceptibility to MS, reside within the MHC. This supports the concept that there is an immune component to the disease. 

One of the most consistent genetic variant linked to MS susceptibility is HLADRB1*1501.(This one variant that forms the DR2 serotype-i.e. a typethat was originally defined by antibodies) This is the first beta (B) chain of  HLA-DR of the first variant of the 15th cluster of variants. HLADQb*0302 is a second variant of the the third cluster of variants of the beta chain of HLA-DQ.  This latter molecule is linked to the development of type 1 diabetes. 

When a protein is broken down it is more likely to associate and load into certain MHC molecules because of their properties such as acid amino acids attach to basic amino acids. Therefore if a protein is a target for autoimmunity when it breaks down it will associate with certain MHC variants and this is how genetic linkage to disease occurs.
So ifsay when a protein gets broken down it gets clipped into peptides (straight coloured bits). That can preferentially associated with one type of HLA.

In MS this is often DR2. That sardinians have MS that are associated with DR4 could suggest that they are recognising either (a) a different target or (b) a different part of the same target. This could be because the genetics of the sardinians are a bit different and could say breakdown the myelin in a different way and so the peptide formed no longer binds to DR2 but it can bind to DR4 and this may be the combination that causes autoimmunity. HLA-DR4 is also associated with the development of other suspected autoimmune diseases notably Rheumatoid Arthritis and type I diabetes. It is of interest that Sardinian people also have a higher risk of diabetes as well as an increase risk of MS about 150 in 100,000 (as occurs in UK) compared to about  95 in 100,000 in central Italy, despite being an island in the Sun.

Wonder what the rate of MS is in Sardinian expats that move North before age of 15, would it be higher than 150 per 100,000? 

6 comments:

  1. Thanks for your time clarifying this. Does this research include Sardinians with an ancestry from Mainland Italy? So the onset of our MS has more to do with genes than vitamin D, the post that prompted me to raise the question.

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    1. I am no expert and if we there is a specialist that would care to comment. I think that MS genes will have a big part to play as it dictates your biology, the risk factors then act on this biology. But remember these factors play a massive role as 70% of identical MS twins do not get MS despite the same genes. Vitamin D has its part to play.

      Obviously Sardinia is does not fit with the hgh sunshine low MS idea,but then again the Norwegians with low MS risk and low sun does not fit, until you bring in Fish eating into the equation.

      Risk to MS is a complex interaction of genes verses infection, verses environment verses diet verses behaviour and I do not know the answer

      http://www.ncbi.nlm.nih.gov/pubmed/23998938
      We performed a systematic review to determine the MS epidemiology reported on prevalence, incidence, environmental factors, treatment, social consequences of MS and neurological disability or progression among MS-affected people. We found information about high MS prevalence in Sardinia, Sweden or Sicily, effects of MS treatment in United States of America, Italy or Germany and environmental factors taking into account as MS risk factors. We concluded that there were many description of MS status in particular countries but they were often insufficiently detailed and not uniform enough to compare it.

      As to which sardinians get MS and their ancestry I don't know without reading more. I doubt it is clear cut.

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  2. So, my father came from Naples, (close to Sardinia), and I was born and bred in England.
    At age 25 I developed type I diabetes, (late onset diabetes), and developed MS 6 years later. Neither disease affected me much for 10 years, although now I have a slow progression of both, in the case of MS it is SPMS.

    When do Sardinians develop diabetes? Are they late onset too?

    Late onset to me suggests a viral link!

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    1. The data suggests that Sardiania get childhood diabetes more often than mainland italy, so there seems to be a range of age of onset

      http://www.ncbi.nlm.nih.gov/pubmed/10869327

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  3. If adaptive immunity is involved HLAs will be a big factor. Does anyone find it interesting that the age of roughly 30 is the magic number for MS? Not to say that other ages are excluded but does anyone have an idea why or can share a link to a paper. Other autoimmune diseases seem to follow. Thanks

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