The lupus susceptibility allele DRB1*03:01 encodes a disease-driving epitope

People with lupus experience their own immune systems attacking their tissues and organs. This disease can result in severe illness and even death caused by major inflammation in the vital organs. There are four kinds of lupus. The most common type of lupus is systemic lupus erythematosus, which is at least partially a genetic condition. A type of lupus that only affects the skin is called cutaneous lupus. A condition known as drug-induced lupus is brought on by specific prescription medications. Infants of women with lupus may experience a rare disease called neonatal lupus.

Systemic lupus erythematosus was the focus of this research. Having a genetic mutation known as HLA-DRB1*03:01 puts people at a higher risk of developing systemic lupus erythematosus.

Researchers identified the molecular mechanism used by the genetic risk factor mentioned above (HLA-DRB1*03:01) for lupus's ability to cause disease.  They discovered that a HLA variation that codes for interferon gamma (IFN-γ) can set off a chain of molecular and cellular events that will result in the inflammatory symptoms experienced by those afflicted with this disease. IFN-γ is a multipotent protein that affects many different cell types by directly influencing the expression of genes to induce or inhibit a wide range of cellular processes. 

This discovery does not present a cure for lupus in itself, but gives researchers a new target from which to develop safer and more effective treatments for this disease. 

Abstract
The HLA-DRB1*03:01 allele is a major genetic risk factor in systemic lupus erythematosus (SLE), but the mechanistic basis of the association is unclear. Here we show that in the presence of interferon gamma (IFN-γ), a short DRB1*03:01-encoded allelic epitope activates a characteristic lupus transcriptome in mouse and human macrophages. It also triggers a cascade of SLE-associated cellular aberrations, including endoplasmic reticulum stress, unfolded protein response, mitochondrial dysfunction, necroptotic cell death, and production of pro-inflammatory cytokines. Parenteral administration of IFN-γ to naïve DRB1*03:01 transgenic mice causes increased serum levels of anti-double stranded DNA antibodies, glomerular immune complex deposition and histopathological renal changes that resemble human lupus nephritis. This study provides evidence for a noncanonical, antigen presentation-independent mechanism of HLA-disease association in SLE and could lay new foundations for our understanding of key molecular mechanisms that trigger and propagate this devastating autoimmune disease.

Miglioranza Scavuzzi, B., van Drongelen, V., Kaur, B. et al. The lupus susceptibility allele DRB1*03:01 encodes a disease-driving epitope. Commun Biol 5, 751 (2022). doi.org...

The full study is at Nature Communications Biology. Let me know if you cannot view the study and I will get you a link to a shareable PDF. The link provided in this OP opens at the Nature website and is not a PDF.


ETA: Before going to bed at night, I usually skim the most recent medical research and read a full study or two. If you'd like me to possibly make a thread about a condition that interests you, let me know, and I will make a list of things to be on the lookout for. I'm going to try to make a few of these types of threads a week.

I have a stat 4 snp heterozygous for Lupus in my data, not too bad being yellow, but the TNPO3 rs10488631 snp is red as hell. There is one yellow in the snps associated with HLA-DRB1 but there was no collection of the data for the other snps in that group...so I have no idea if it applies to me.

My Cousin died of Lupus, and I get symptoms that could be related to Lupus symptoms if I consume certain foods that raise my histamine levels. I did see first hand what Lupus did to my cousin when he first found out he had it long ago, he had problems with his hand and some spots on other parts of his body which he just told me about but I did not actually see. I have increased susceptability to it but have never had a doctor actually say it was related to Lupus when I had these events effecting my skin and organs, because I never went to a doctor when I got them, but did inform them of my family history of multiple autoimmune diseases including this one when I used to fill out the form before appointments. I also put down the RA and ankelosing spondylitis family history. I have tried to watch what I ate that negatively effected me since I was a teenager, but things do happen when you get older, keeping the autoimmune issues at bay seems to get more complicated when you get old. You would think it would be less of a problem when you get older and your immune system gets less power, but it doesn't seem to work that way for some reason.

I suppose ancestry can't collect all the snps when you pay eighty bucks for a test, including shipping of the sample both ways.

a reply to: rickymouse

I'm sorry to hear about your cousin. How long ago did he die?

The incidence of lupus has been steadily increasing since the 80s. I see lupus as a condition where environmental factors interact with genes for the disease to show. Diet does seem to have a major role in the severity of symptoms, and most people are able to better manage this disease by replacing pro-inflammatory foods with anti-inflammatory ones. You and I have talked about diet in the past, and I think that you do likely stick with eating all of the right things for the most part. Keeping an optimal vitamin D level, taking probiotics, and eating foods rich in Omega-3 and iron can often help ease the symptoms. Some of the foods that shouldn't be eaten are gluten, added sugars, high-fructose corn syrups, processed foods, saturated fats, cholesterol, sodium, alfalfa sprouts, and garlic. If you think that you do have lupus, I suggest letting the doctor see you when you have symptoms. However, if your doctor has been giving you regular CBC lab work, there should already be some tests included that could detect active autoimmune disorders, but the results could also show normal since you are not actively symptomatic. Going whenever you have symptoms could produce some lab results which shed some light on what you have going on.

You and I have talked about this before, but I will say it for the benefit of the other readers. Having genetic variations associated with disease does not necessarily mean that you will have that disease. There are often multiple alleles involved in manifesting a disease, and also there are often environmental factors required, too.

a reply to: tamusan

Most of the genetic diseases have triggers that increase the risk of the disease becoming a problem. If the people do not consume the triggering food, the disease is not yet a disease, just a susceptability.

Paragraph 5 of this article is pertinent. www.sciencedaily.com...

If you have autoimmune disease risk, you sure in the hell do not want to eat a lot of foods that boost immunity, because feeding foods that increase replication or stimulating the immune system to fight something that you might not be in risk of getting can trigger it to build too many cells that can attack your own body. This might be the reason I get a cytokine storm from the flu and DTAP shot. This immune system going berserk when I get those vaccines is why I should definitely not get the covid vaccine too. Did I have bad reactions to early childhood vaccines...don't know, I wasn't paying attention when I was young. I also have my immune system over react from bad slivers or ingrown hairs....which sucks.

I took a class on metabolomics years back and another on epigenetics and those classes stated precisely that genetics and diet selection are connected to keep genetic diseases from expressing themselves, but there was not yet enough research to narrow things down. Foods contain multiple chemistries and ancestral diet does make a difference. Whole families are sick all the time because they do not eat the foods that keep them healthy...Hint, sometimes foods they call super foods actually make these things worse, and lots of times cooking veggies helps to reduce the risk of a disease or condition forming.

My cousin who had the lupus had a small farm and they ate lots of tomatoes, which can cause histamine levels to go up which can increase the risk of lupus becoming a problem. The tomatoes were used in spaghetis and with pastas which is a double whammy. I have problems when I eat tomatoes more than once a week, the wife doesn't have much problems at all with tomatoes...I love tomatoes, but should not eat them very often and do screw up occasionally and get little sores on my forehead and some other parts on my body. I identified this years ago when I had a big pile of tomatoes and ate lots of them. I never ate tomatos very often when we went out and ate at restaurants, the wife ordered those kind of dishes, I ordered fish and chips or maybe a fish sandwich or a plain burger...gave up eating ketchup fifty years ago, never knew why I quit eating it, just did. Burger king was my first fast food choice, get it your way, no cheese and only lots of onions on the burger. McD's burgers were gut bombs, they just seemed to sit in my stomach for the rest of the day...something to do with something in the bun I think.

My cousin died about twelve years ago, he was aware he had Lupus for about maybe ten years before that. No doctors ever mentioned anything about diet to him. The thing is that tomatoes are touted as a super food even though they can cause some Chronic problems if you eat too much.