The study of patients with Recombination-Activating Gene (RAG) deficiency and other forms of combined immunodeficiency (CID) has revealed distinct abnormalities in central and peripheral T- and B-cell tolerance as the key. Severe viral or vaccine-induced infection is described, with fatal sepsis in childhood. Autoimmune features are also described, with immunoglobulin levels, vaccine responses, and lymphocyte numbers being variably absent, low, or normal. Missense mutations in RAG have been described in the results.
Patients with RAG deficiencies represented a broad spectrum of RAG deficiencies: SCID, OS, LS/AS, and CID. Three novel mutations in the RAG1 gene and one in RAG2 were reported. RAG deficiency may manifest with a broad range of clinical phenotypes, ranging from severe, early-onset infections to inflammation and severe combined immune deficiency. These data identify abnormal selection of TCR and Ig genes targeted to V(D)J recombination as a novel mechanism by which hypomorphic RAG mutations may impinge on T and B cell.
The recombination-activating genes (RAGs) encode parts of a protein complex that plays important roles in the rearrangement and recombination of the genes encoding. In this review, the extended spectrum of RAG deficiencies and their associated clinical and immunological phenotypes in humans are reviewed. Circulating T cells are absent or very low in patients with RAG deficiency, manifesting as typical SCID. Babies born with SCID appear healthy at birth but are unable to fight infections.
The RAG2 gene provides instructions for making a member of the RAG complex, which is active in immune system cells. Clinical presentation of RAG-deficient patients includes recurrent or severe respiratory infections and generalized infections.
| Article | Description | Site |
|---|---|---|
| RAG Deficiency: Two Genes, Many Diseases – PMC | In patients with RAG deficiency, circulating T cells are either absent or present at very low levels, which manifests as typical SCID (Fig. 2). An exception is represented by the case of… | www.ncbi.nlm.nih.gov |
| Identification of RAG-like transposons in protostomes … | by EC Martin · 2020 · Cited by 22 — The evidence suggests that RAGL transposons were active during the evolution of bilaterians, undergoing multiple duplication and loss/fossilization events. | mobilednajournal.biomedcentral.com |
| RAG genomic variation causes autoimmune diseases … | By N. Haque · 2023 — Our research has identified mutations across different protein domains that impair RAG activity, thereby dysregulating the immune system due to altered… | www.sciencedirect.com |
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What are the symptoms of RAG1 deficiency?
Severe combined immunodeficiency due to complete RAG1/2 deficiency is a rare, genetic T-B- severe combined immunodeficiency disorder due to null mutations in recombination activating gene (RAG) 1 and/or RAG2 resulting in less than 1% of wild type V(D)J recombination activity. Patients present with neonatal onset of life-threatening, severe, recurrent infections by opportunistic fungal, viral and bacterial micro-organisms, as well as skin rashes, chronic diarrhea, failure to thrive and fever. Immunologic observations include profound T- and B-cell lymphopenia, normal NK counts and low or absent serum immunoglobulins; some patients may have eosinophilia.
The documents contained in this website are presented for information purposes only. The material is in no way intended to replace professional medical care by a qualified specialist and should not be used as a basis for diagnosis or treatment.
What is the difference between RAG1 and RAG2?
Lymphocytes express RAG1 and RAG2 during the assembly of their antigen receptors. These enzymes have different levels of expression during different stages of B-cell and T-cell antigen receptor assembly. RAG1 is active at early lymphoid development stages, while RAG2 is turned off during lymphoid cell proliferation after successful initial gene rearrangements. RAG2 expression increases and decreases more drastically than RAG1 in both immature B-cells and thymocytes, likely due to a posttranscriptional mechanism.
After successful receptor gene rearrangement in immature B-cells, production of RAG1 and RAG2 continues. If the B-cell is not self-reactive, RAG protein production decreases but does not completely stop until the B-cell is fully mature. However, if the B-cell is self-reactive, RAG protein production continues at the same levels, and receptor gene rearrangement continues as long as there are available and unused V and J gene segments.
Both RAG1 and RAG2 are necessary for V(D)J recombination, which involves cleaving DNA at recombination signal sequences and catalyzing the formation of the DNA hairpin. Two RAG protein complexes recognize and align the two recombination signal sequences, with RAG1 directly recognizing the recombination signal sequences. The RAG proteins help hold the DNA ends together, and RAG1 and RAG2 nick open the DNA hairpin with a single-stranded break, resulting in the recombination of V, D, and J gene segments.
How do you treat rag deficiency?
Hematopoietic stem cell transplant (HSCT) is the only cure for patients with severe manifestations of RAG deficiency; however, outcomes are suboptimal with mismatched donors. Gene therapy aims to correct autologous hematopoietic stem and progenitor cells (HSPC) and is emerging as an alternative to allogeneic HSCT.
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What is RAG1 and 2 deficiency?
Recombination-activating genes (RAG) 1 and RAG2 are essential for initiating the molecular processes that lead to lymphocyte receptor formation through VDJ recombination. Nonsense mutations in RAG1 / RAG2 cause the most profound immunodeficiency syndrome, severe combined immunodeficiency (SCID). Other severe and less-severe clinical phenotypes due to mutations in RAG genes are now recognized. The degree of residual protein function may permit some lymphocyte receptor formation, conferring a less-severe clinical phenotype. Many non-SCID phenotypes are associated with autoimmunity. Recent findings into the effect of mutations in RAG1/2 on the developing T- and B-lymphocyte receptor give insight into the development of autoimmunity. This article summarizes recent findings and places the genetic and molecular findings in a clinical context. A spectrum of less-severe clinical phenotypes is now recognized to be due to mutations in RAG genes, with recent understanding of the impact of mutations on protein function helping to explain some of these features.
What is the function of the rag complex?
V(D)J recombination is a process where the RAG complex binds to a DNA segment called a recombination signal sequence (RSS) and makes small cuts to separate and move the segment. This process of DNA rearrangement within B cells and T cells is repeated multiple times in different areas, arranging the V, D, and J segments in various combinations. This process helps the body fight infections efficiently.
Omenn syndrome, a severe combined immunodeficiency (SCID) characterized by a lack of immune protection from foreign invaders, is caused by at least 70 mutations in the RAG1 gene. These mutations impair RAG complex formation and function, leading to reduced V(D)J recombination and limited protein diversity on B and T cell surfaces. This results in frequent, life-threatening infections.
The decrease in lymphocyte function leads to a reduction in B cell numbers, but the number of T cells is typically normal. The abnormal T cells attack the body’s own cells and tissues, accounting for the autoimmune features of Omenn syndrome. Without treatment, Omenn syndrome is often fatal in infancy.
Why is RAG important?
Ethical considerations. RAG helps address ethical considerations by providing transparency and control over the information used in AI-generated outputs. Its ability to retrieve contextually relevant information improves the accuracy of both generic and fine-tuned foundation models. Ideally, the RAG workflow includes links to the retrieved context within the LLM response, allowing users to validate the responses. This approach serves as a means to combat bias and protect against hallucinations.
RAG also enables data lineage for LLMs by offering the ability to trace the origin and history of the data used in AI-generated outputs. By retrieving information from specific sources within proprietary data repositories, RAG provides transparency and accountability, ensuring that AI-generated content is grounded in verifiable and trustworthy data sources.
. Onna has created an internal Slackbot using a RAG workflow, which enables team members to search for internal information and provides reference links.
How a lack of rag protein results in the phenotype observed in baby joe?
In the absence of RAG proteins, V(D)J recombination cannot occur, leading to a severe reduction in the diversity of B-cell and T-cell receptors. This results in an immune system that is unable to effectively recognize and respond to foreign antigens, leading to the immunodeficiency observed in Baby Joe.
Are RAG1 and RAG2 enzymes?
RAG1 and RAG2 are two proteins essential for immunoglobulin and T-cell receptor gene recombination. They work closely together in receptor gene recombination, making them the lymphoid-specific parts of V(D)J recombinase. All species carrying out V(D)J recombination have RAG1 and RAG2, with their expression levels correlated directly with V(D)J recombination activity. RAG1 contains most or all of RAG1/RAG2 V(D)J reconbinase’s active site, while RAG2 is essential in joining DNA segments during V(D)J recombination.
In vitro, the RAG protein can act as a transposase, suggesting that vertebrates adapted the protein to allow V gene segment recombination, leading to the vertebrate adaptive immune system. Developing lymphocytes express RAG1 and RAG2 while assembling their antigen receptors, with different levels of expression during different stages of B-cell and T-cell antigen receptor assembly. Lymphocytes actively express RAG1 and RAG2 at early lymphoid development stages, turn off RAG1 and RAG2 expression during lymphoid cell proliferation, and activate RAG1 and RAG2 expression when lymphoid cells stop dividing and go on to make final gene rearrangements.
After successful receptor gene rearrangement in immature B-cells, production of RAG1 and RAG2 continues. If the B-cell is not self-reactive, production decreases but does not completely stop until the B-cell is fully mature. If the B-cell is self-reactive, RAG protein production continues at the same levels, and receptor gene rearrangement continues as long as there are available and unused V and J gene segments. In thymocytes, the presence of pre-T-cell receptors triggers the repression of RAG expression during the proliferative phase, preventing rearrangement of the α chain locus.
What do RAG enzymes do?
RAG enzymes are multi-subunit complexes that cleave a single double-stranded DNA (dsDNA) molecule between the antigen receptor coding segment and a flanking recombination signal sequence (RSS). They do this in two steps: introducing a ‘nick’ in the 5′ end of the RSS heptamer, leaving behind a specific biochemical structure on this region of DNA. The next step couples these chemical groups, binding the OH-group to the PO 4-group, producing a 5′-phosphorylated double-stranded break at the RSS and a covalently closed hairpin at the coding end. RAG proteins remain at these junctions until other enzymes repair the DNA breaks.
RAG proteins initiate V(D)J recombination, which is essential for the maturation of pre-B and pre-T cells. Activated mature B cells also possess two other remarkable, RAG-independent phenomena of manipulating their own DNA: class-switch recombination (AKA isotype switching) and somatic hypermutation (AKA affinity maturation). Current studies indicate that RAG-1 and RAG-2 must work in a synergistic manner to activate VDJ recombination. RAG genes may not only assist in VDJ recombination but directly induce the recombinations of the VDJ genes.
RAG proteins are fairly large, with mouse RAG-1 and mouse RAG-2 having a core region with most of the DNA cleavage activity. The RAG-1 core contains three acidic residues in the DDE motif, critical for nicking the DNA strand and forming the DNA hairpin.
How do RAG1 and RAG2 ensure that recombination takes place at antibody gene segments?
The study focuses on the roles of RAG1 and RAG2 proteins in V(D)J recombination, which initiates recombination by introducing double-strand breaks at the border between a recombination signal sequence (RSS) and a coding segment. The researchers compared the DNA binding activities of RAG1 alone and RAG1 plus RAG2 using gel retardation and footprinting analyses. They found that RAG1 exhibits a preference for binding DNA containing an RSS over random sequence DNA. However, the presence of both RAG1 and RAG2 results in the formation of a more stable and specific RAG1-RAG2-DNA complex, which is active in V(D)J cleavage.
The study also highlights that biologically effective discrimination between an RSS and nonspecific sequences requires both RAG1 and RAG2. RAG1 can bind to DNA without a divalent metal ion and does not require the presence of a coding flank sequence. Footprinting of the RAG1-RAG2 complex with 1, 10-phenanthroline-copper and dimethyl sulfate protection revealed that both the heptamer and the nonamer are involved in the recombination reaction.
The recombination reaction can be divided into two stages: first, double-strand breaks (DSB) are created at the border of the RSS and coding segment, while signal ends are blunt, 5′-phosphorylated molecules. In the second stage, broken molecules are processed and ligated to form signal and coding joints, introducing junctional diversity. The first stage of recombination is mediated by lymphoid-specific genes RAG1 and RAG2, while later stages require factors involved in DSB repair.
Where is RAG1 and RAG2 found?
Recombination activating genes (RAG)1 and RAG2 are expressed in developing B and T lymphocytes and are required for the rearrangement of antigen receptor genes. In turn, RAG expression is regulated by the products of these assembled immunoglobulin (Ig) and T cell receptor (TCR) genes.
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📹 Dermatologist Break Down The Body Wash Versus Bar Soap Debate
Erin Gilbert is a practicing dermatologist in New York City. Here, she explains why she uses body wash instead of bar soap.
For smooth glowing skin: 1 – I drink good amount of water. It aids in the process. Drink at least 2 liters water per day. 2 – Daily, I cleanse my face with riceeberry face wash from litleextra. Although I occasionally skip this step due to impatience. It’s effective, but consistent daily application is necessary. 3 – I prevent using any soap, etc. on face. 4 – I avoid junk food. 5 – I engage in 30 minutes of exercise daily. All together, these practices contributed to my clear, radiant skin free from acne, dark spots, and pimples.
I am a soap maker and I feel extremely confused. Madam dermatologist, after the saponification process, no lye is present in the soap. After that chemical reaction, oil and lye become a new substance we know as soap. After soap is formed, it produces natural, moisturizing glycerin. A bar soap with over 50% coconut oil will definitely be drying because that’s it’s nature, but a balanced bar of soap shouldn’t dry you out. Now liquid body was is basically detergent and the reason they add so much extra (expensive) crap is because DETERGENTS ARE DRYING.
after traveling for my job for about 7 years, I’ve accumulated an entire bathroom drawer of those little bars of soap that the hotel gives you, they work perfectly and don’t cost me a dime, and there’s no bottle to end up in a landfill. I have pretty resilient skin, so I’m definitely not the majority, but it works for me and I’ll never use anything else.
What the fuck. She knows shit all about soap if she thinks there’s ANY lye remaining after the saponification process. Basically, with that one comment she’s completely exposed that she’s not educated on the very thing she’s being presented as an expert opinion. How do I know? I ran a soap making business for years. Saponification is not a complex concept, it’s a basic calculation. A calculation used to ensure that not only is there no lye left in the final product, there’s actually a buffer of oils left over. And I’m a body wash user nowadays.
I don’t think one is better than the other…It all depends upon each individual’s skin type and how they wish to feel… I personally prefer body wash, but ONLY body wash that makes me feel clean and smooth…NOT GREASY…My 2 favorites right now are OLAY OUTLAST ROSE…(white bottle with pink top) It contains NIACINAMIDE, which gently exfoliates the skin and leaves me feeling clean…My second favorite is DOVE ANTIBACTERIAL BODY WASH…Neither contain heavy oils or petrolatum, and both smell great…I look for a good, strong scent and no skin clogging ingredients…These 2 fit the bill 👍
It’s funny when you see comments about a bar soap that helps your skin not be so dry. What soap are you using? I went to buy a good soap, spend 8 $ for one bar of head and face bar soap. After a few days, I have got some skin problems like pimples all over the place I used that face-friendly active coal soap. So I check the ph level and it was 9.5 almost pure lay. This soap was recommended for the head and face. Then I try to find soap with a ph around 7 or 7.5. Good luck with that. I cant check ph in the store. To make the story short there is no soap with less than 8. That’s why I prefer body wash, all of them have ph = 7
Most if not nearly all body washes are scented, which can effect a female’s part. Maybe it can for males, too, I don’t know, but it can cause infections and stuff like that. Also, body wash is worse for the echo system and literally so much more expensive than 8 bars of soap that will last so much longer than that one bottle. Bars of soap are 1. Better for your skin, 2. Better for the echo system, 3. Can be rubbed on a loofah fine, 4. Has a light, not too strong scent that won’t effect others. And, the list goes on. I used to use body wash a long while ago, ran out of that and switched to bars of soap and found out it was so much better. You’re welcome.
I had switched to bar soaps and used for years and noticed the aging. My skin was just not good bc my skin does not handle soaps, detergents and cleansers welll. For me bar soaps are typically too drying in comparison to body wash. I use cleansing oils and balms now. I feel so squeaky clean bc they really pull things out of the pores. And I get enough rinse off that I don’t have an oily after feeling. I really don’t think ppl should be using anything else besides that. All these skincare and cosmetic stuff are disrupting hormones and causing illnesses. I’ll stick with my oils that have very few natural ingredients. And u can use them anywhere. There’s no need for a soap for different parts of your body 🤷🏽♀️
I’m sorry but bar soap is way better. Just put on lotion after. I actually converted to bar soap after all of the body washes I got were drying my skin. Also those big puffy loofahs are full of bacteria. I’d recommend using a natural loofah rather than synthetic and making sure to change it every few months
I have been using homemade bar soaps for over one year now. These are the one’s my wife creates from scratch ingredients. So I ran out recently, and used Targets Methos Men Bodywash, which frankly I do love the smell. However the difference was amazing. The body wash was slick, smelled good, but just didn’t do anything for my skin. My bars coddle me with some substance. They have a creaminess, and actually a certain amount of ‘friction’ on the skin that really gets me seriously clean. I’m not going back.
This sounds like when the diamond mining companies were promoting that engagement proposal should come with a HUGE diamond ring that cost 2-3 months of salary. She’s trying to make us believe that body wash (cost more than bar soap) is the way to go. It’s up to us to make a conscious decision that fit our life style.
I’ve used shampoo until the late 90’s when body wash was becoming more of a thing. I never liked bar soap because it leaves a film on you or something, Like feeling sticky. A little over a month ago I went to an Amish bent and dent with my wife, they had Amish hand made bar soap. I tried it and it’s the best soap I’ve ever used, it doesn’t have that sticky feeling and my skin feels nice. It’s $1 per bar, there is another Amish store that has the same hand made soap $2.25 for four.
She also didn’t mention Castillo which is not lye based and supposedly much more environmentally friendly comes in different scents- I love the peppermint it smells divine and feels great on your skin you can use it for so many different things don’t know if anyone else mentioned this in the comments I tried to look
The issue with body wash that I was educated on once I went to school for my profession, But also was literally an experience that I didn’t connect the dots to was this, Body wash smudges around your existing protein and bacteria so imagine that protein from your stinky areas just being erupted around instead of actually washed off. I think the key would be moisturizing after you’ve used your bar soap. If you want to use a body wash for a fragrance and a in shower moisturizer after you use the bar soap good idea for you.
Wrong. Handmade bar soap is FAR LESS DRYING than any liquid soap. It’s fully made of luxurious butters and oils. Even aloe Vera, or goat milk. Plus, I always use silk in mine as well to make it extra softening and it’s far nicer than the chemicals used in liquid soap. That’s actually the reason I began making my own. My skin was so dry from soft soap because of the chemicals. Now that I’m a soap maker, my skin is soft and not dry at all.
To clean ones body, one may use anything. Bar soap or body wash. To wash away extra oil and to feel clean men mostly prefers bar soap ( dry ), women may prefer body wash ( moisture ); however it all depends on the USAGE of body lotion to determine which sex is going to produce more laundry to wash!! And thus drive up the inflation.
I don’t know what this lady is talking about bar soaps are way better, first off they last longer and are easy to buy and store in bulk. Secondly you still use a loofah or what ever to wash with, rub soap on you then rub it on the loofah to make bubbles and then wash yourself. Thirdly they only make you feel “dry” for a few seconds after showering. If anything they help encourage you to put lotion on Bars over liquid, easy choice
I’m using bar soaps. There are a lot of newer ones that aren’t drying. Anyways, you’re not supposed to scrub your entire body. Just wash the parts with soap that need to be washed. Water will clean the rest. We as Americans, are washing our bodies far too often. Your skin will improve like mine has if you stop excessively washing it.
Nah bar soap strips your skin of it’s natural oils and leaves your skin feeling gritty! Using an exfoliating loofah with body soap is the way to go even dove leaves my skin feeling stripped of oils where my skin once the soap is washed away gets stuck on itself if I was trying to glide one arm across the other. It’s just facts 🤷♂️
I know the reason people use body wash these days. The smell of it lasts for weeks, so they don’t have to shower daily. The problem is, I can smell them coming three blocks away, and in their own opinion they smell great. I have to work near these people all day long, and I think the smell is absolutely nauseating! So before you use that stuff, consider that others may not find it so “great smelling”. Especially towards the end of the week when your body odor begins to over power the body wash!
No disrespect but you can keep your poofy loofah and your body wash all to yourself I would even let you buy it all because using Ivory soap or Yardley soap is the best way to go and there’s nothing wrong with being squeaky clean and feeling a little dry and putting on moisturizing oil afterwards I don’t even use cream anymore because of what’s now I use Aveeno oil and it’s perfect and my skin has never felt healthier and besides you can get a 10 bar pack of Ivory soap for under $5…10 BARS…
FYI I get dry skin from dove soap and “some coconut oil”? really girl? the coconut oil is the cleansing ingredient in the soap that can be substituted by the cheaper palm oil. You have no idea what ya talking about when it comes to soap.And btw, not all body washes are made with soap, many are made with surfactants because is cheaper and faster and to achieve a ph under 7 that you cannot get by traditional methods of making soap.
she’s annoying and has no arguments, just blabbering about her own opinion. Soaps are much more eco-friendly, more natural and clean the skin from dirt and oil million times better. Body washes are watered down detergents with tones of chemicals. a way to sell you lees product for more money. I’ve been a body wash girl all my life, personal friend I know that is a dermatologist told me in confidence to ditch it all and switch to soaps for body. since I switched to soaps my skin regenerated. my back shoulder acne cleared up, my skin is softer I never felt so clean after a shower as I do with soap, you can feel i removes all the gunk from your skin, and only then you realize how much shower gels use to left residue and film on your skin and clog your pores. first time I showered with soap I was shocked I felt like I bathed for the first time in 10 years, and I always showered 2 times a day lol. that’s how clean my skin felt. there are some amazing soaps now for sensitive skin that also hydrate.. try for yourself. not to mention its 100 times cheaper!!!
What kind of a DOCTOR are you if you don’t adress the EXTENSIVE AMOUNTS OF PLASTIC molecules in body wash (shampoo, tooth paste) that have a negative HORMONAL effect on your body (because you use it every day and it is getting absorbed by your skin, your gums, your mouth and you even get small portions of it into your nose and stomach by breathing in the aerosole and swallow tooth paste) and I don’t even want to get into the environmental debate here. Don’t use body wash, and especially don’t give it to your children (in fact try to have them avoid plastics as much as possibble), because plastic messes with the hormonal balance of you and your children’s bodies and cause all kinds of issues from minor things to straight up testicular underdevelopment, resulting in an underproduction of testosterone in boys and men and similar effects in girls and women messing with their estrogen balance. This is a serious matter, and all she adresses is the moisture?!
My name is Rhonda Pickett I found out a little history about myself I am sunderthein a far far territory it was life and death situation and I resurrected with a curve and showed up on Earth I’m hoping to close some the investigations and bring things to a close I’m a hassien- Mexican havannua oosu moo Loren vietnesse arbic all wrong dry