#antigen recognition

[er-cryptid]

Patreon

[covid-safer-hotties]

Fourth dose bivalent COVID-19 vaccines outperform monovalent boosters in eliciting cross-reactive memory B cells to Omicron subvariants - Published Aug 8, 2024

Remember when that kid called me an uneducated idiot when I suggested that monovalent vaccines provide less long-lasting broad protection from all covid strains? I present Scientific Catharsis

Abstract Bivalent COVID-19 vaccines comprising ancestral Wuhan-Hu-1 (WH1) and the Omicron BA.1 or BA.5 subvariant elicit enhanced serum antibody responses to emerging Omicron subvariants. Here, we characterized the RBD-specific memory B cell (Bmem) response following a fourth dose with a BA.1 or BA.5 bivalent vaccine, in direct comparison with a WH1 monovalent fourth dose. Healthcare workers previously immunized with mRNA or adenoviral vector monovalent vaccines were sampled before and one-month after a fourth dose with a monovalent or a BA.1 or BA.5 bivalent vaccine. Serum neutralizing antibodies (NAb) were quantified, as well as RBD-specific Bmem with an in-depth spectral flow cytometry panel including recombinant RBD proteins of the WH1, BA.1, BA.5, BQ.1.1, and XBB.1.5 variants. Both bivalent vaccines elicited higher NAb titers against Omicron subvariants compared to the monovalent vaccine. Following either vaccine type, recipients had slightly increased WH1 RBD-specific Bmem numbers. Both bivalent vaccines significantly increased WH1 RBD-specific Bmem binding of all Omicron subvariants tested by flow cytometry, while recognition of Omicron subvariants was not enhanced following monovalent vaccination. IgG1+ Bmem dominated the response, with substantial IgG4+ Bmem only detected in recipients of an mRNA vaccine for their primary dose. Thus, Omicron-based bivalent vaccines can significantly boost NAb and Bmem specific for ancestral WH1 and Omicron variants, and improve recognition of descendent subvariants by pre-existing, WH1-specific Bmem, beyond that of a conventional, monovalent vaccine. This provides new insights into the capacity of variant-based mRNA booster vaccines to improve immune memory against emerging SARS-CoV-2 variants and potentially protect against severe disease.

One-sentence summary Omicron BA.1 and BA.5 bivalent COVID-19 boosters, used as a fourth dose, increase RBD-specific Bmem cross-recognition of Omicron subvariants, both those encoded by the vaccines and antigenically distinct subvariants, further than a monovalent booster.

[a-typical]

Will these vaccines provide immediate protection?

Vaccines contain an active ingredient used to trigger generation of immune memory. That active ingredient, the antigen, is what initiates the immune response, starting with innate immune recognition and ending with adaptive immunity generation (read here for a more detailed summary on viral immunology).

Adaptive immune response leads to antibody by plasma cells, activation of helper T cells and cytotoxic T cells, and generation of memory B and T cells.

This process takes time, roughly 2 weeks after we encounter the foreign invader (either the vaccine antigen or an actual pathogen). Once memory B and T cells are created, the response to a second encounter is much quicker because all the preparation is already done. The adaptive immune system is ready to go: B cells can start spitting out antibodies, helper T cells can augment the B cell responses, and cytotoxic T cells can directly kill infected cells to limit the spread of infection.

Vaccines train the immune system in advance of an infection.

The ability to immediately respond means that even if virus infects you after vaccination, your body can fight it more quickly, reducing viral load, lessening disease severity, and decreasing the likelihood of more serious illness or death.

[cbirt]

The launch of AlphaFold signaled a revolution in computational modeling: armed with new knowledge of protein structures and unencumbered by limitations on resources and time, scientists were able to use the tool to further their understanding of protein structure, functionality, and interactions. However, AlphaFold’s success in the realm of antibody-antigen modeling is limited. A new study from the University of Maryland evaluates its accuracy and provides new insights into the factors influencing protein modeling.

Antibodies are an important part of the immune system and defend the body from a host of pathogenic organisms due to their high specificity and affinity to antigens. Usually, these targets are engaged through the use of hypervariable CDR loops present in the variable domain. The high specificity of these interactions makes the development of antibodies an important consideration in fields like therapeutics and vaccine development.

The high-resolution structure development of antibody-antigen complexes has served to significantly enhance our understanding of immunity and its underlying mechanisms, allowing for the design of immunogens and antibodies. However, experimental methods for structure determination pose many challenges and constraints on resources and time, often making it infeasible to obtain experimentally derived characterizations for most complexes. In order to fill this need, an array of computational tools have been created – general methods for protein-protein docking have been utilized but haven’t been very successful due to their failure to consider the mobile nature of important CDR loops. Hence, tools have been developed specifically to model antibody-antigen complexes, but obtaining accurate predictions remains challenging.

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[science-sculpt]

The Immune System's All-Star Team: The Mighty Cells That Protect You

Your body is like a bustling city, constantly facing threats from outside invaders like viruses and bacteria. Thankfully, you have a team of dedicated defenders keeping you safe: your immune cells! Our immune system is a marvel of biological defense, tirelessly safeguarding our bodies from harmful invaders like bacteria, viruses, and parasites. At the forefront of this defense are numerous types of immune cells, each with its unique functions and capabilities. Did you know the average adult has about 2 trillion white blood cells, which contain most immune cells? That's more people than live in China! These tiny warriors come in different shapes and sizes, each with unique superpowers to protect you. Let's meet some of the key players:

The Innate Force: First up, we have the innate immune system. This frontline defense acts fast and nonspecifically, providing immediate protection against any threat. The key players: 1. Neutrophils: Think of these guys as the city's SWAT team. They're the first responders, rushing to attack invaders with toxic chemicals and swallowing them whole with their arsenal of enzymes! These are the most abundant immune cells, are short-lived but highly effective. Unfortunately, they die in the fight, leaving behind a green gooey mess (pus) that signals infection.

2. Macrophages: These are the veterans, the wise generals of the immune system. They go beyond mere engulfing, processing antigens (foreign molecules) and presenting them to other immune cells for recognition and attack. They also act as scavengers, cleaning up debris and orchestrating healing. These are the cleaners and recyclers. They gobble up dead neutrophils, debris, and even worn-out cells, keeping your city sparkling clean.

3. Natural Killer (NK) Cells: These are the ninjas of the immune system. They silently patrol, sniffing out suspicious cells infected with viruses or even cancer and eliminating them with a swift punch. The Adaptive Arsenal:

The Adaptive Arsenal: If the innate system fails, the adaptive immune system steps in. This highly specific defense remembers past encounters and tailors its response to each unique threat. The cells of adaptive immune system are:

B Cells: These are the antibody factories, producing highly specific proteins called antibodies that neutralize pathogens and toxins. Each B cell produces a unique antibody, like a lock and key, targeting specific invaders. They whip up special proteins called antibodies that lock onto specific invaders, like sticky notes, marking them for destruction.

T Cells: These are the generals, coordinating the entire defense. There are different types of T cells:

Helper T Cells: These are the commanders, directing and coordinating the immune response through chemical signals. They activate B cells, macrophages, and other immune cells, orchestrating a multi-pronged attack.

Cytotoxic T Cells: These are the elite soldiers, directly targeting and eliminating infected cells or cancer cells. They recognize and bind to specific enemy markers, unleashing a lethal attack.

Memory T Cells: These are the veterans, remembering past encounters with invaders and helping the immune system respond faster next time.

The Unsung Heroes: Beyond these main players, numerous other immune cells contribute to our defense. These include:

Dendritic cells: These antigen-presenting cells capture and process pathogens, presenting their fragments to T cells for activation. They're like the scouts, gathering enemy intel and relaying it to the command center.

Mast cells: These cells reside in tissues and release inflammatory chemicals in response to allergens or parasites. They're like the alarm system, alerting the immune system to local threats.

Eosinophils: These specialize in fighting parasitic infections, releasing toxic chemicals to neutralize them.

Basophils: These are involved in allergic reactions and contribute to wound healing.

The beauty of the immune system lies in its intricate collaboration. These diverse cell types work together in a complex and beautiful dance, each playing a specific role to achieve a common goal: protecting our health. They communicate extensively through chemical signals, creating a complex network of interactions. Imagine B cells producing antibodies that bind to a pathogen, flagging it for destruction. Macrophages engulf and eliminate the tagged pathogen, while T cells coordinate the attack and eliminate any infected cells. Dendritic cells present captured fragments to T cells, priming them for future encounters. This seamless cooperation ensures a swift and effective response to any threat.

Your immune system is constantly learning. Each time you get a vaccine or fight off an infection, your immune cells create memory T cells, making you more resistant to future attacks. Understanding these cellular heroes can help us appreciate the incredible machinery that keeps us healthy and appreciate the importance of maintaining a strong immune system. It also allows us to make informed decisions about supporting our immune system. Maintaining a healthy lifestyle, getting adequate sleep, managing stress, and consuming a balanced diet can all contribute to a robust immune response.

[bpod-bpod]

Gather Round

The immune system's B cells recognise their foe (antigens) with receptors (also known as immunoglobulin or antibody) on their cell surface. Here, super resolution microscopy combined with 4D image analysis reveals how these receptors on the cell surface localise into clusters as ridges and finger-like projections called microvilli to aid recognition of their targets

Read the published research paper here

Video adapted from work by Deniz Saltukoglu and colleagues

Department of Molecular Immunology, Biology III, Faculty of Biology, University of Freiburg, Freiburg, Germany

Video originally published with a Creative Commons Attribution 4.0 International (CC BY 4.0)

Published in The EMBO Journal, January 2023

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[transgenderer]

Virus latency (or viral latency) is the ability of a pathogenic virus to lie dormant (latent) within a cell, denoted as the lysogenic part of the viral life cycle.[1] A latent viral infection is a type of persistent viral infection which is distinguished from a chronic viral infection. Latency is the phase in certain viruses' life cycles in which, after initial infection, proliferation of virus particles ceases. However, the viral genome is not eradicated. The virus can reactivate and begin producing large amounts of viral progeny (the lytic part of the viral life cycle) without the host becoming reinfected by new outside virus, and stays within the host indefinitely.[2]

Episomal latency refers to the use of genetic episomes during latency. In this latency type, viral genes are stabilized, floating in the cytoplasm or nucleus as distinct objects, either as linear or lariat structures. Episomal latency is more vulnerable to ribozymes or host foreign gene degradation than proviral latency (see below).

Advantages of episomal latency include the fact that the virus may not need to enter the cell nucleus, and hence may avoid nuclear domain 10 (ND10) from activating interferon via that pathway. Disadvantages include more exposure to cellular defenses, leading to possible degradation of viral gene via cellular enzymes.[12]

Proviral latency: A provirus is a virus genome that is integrated into the DNA of a host cell

All interferons share several common effects: they are antiviral agents and they modulate functions of the immune system. Administration of Type I IFN has been shown experimentally to inhibit tumor growth in animals, but the beneficial action in human tumors has not been widely documented. A virus-infected cell releases viral particles that can infect nearby cells. However, the infected cell can protect neighboring cells against a potential infection of the virus by releasing interferons. In response to interferon, cells produce large amounts of an enzyme known as protein kinase R (PKR). This enzyme phosphorylates a protein known as eIF-2 in response to new viral infections; the phosphorylated eIF-2 forms an inactive complex with another protein, called eIF2B, to reduce protein synthesis within the cell. Another cellular enzyme, RNAse L—also induced by interferon action—destroys RNA within the cells to further reduce protein synthesis of both viral and host genes. Inhibited protein synthesis impairs both virus replication and infected host cells. In addition, interferons induce production of hundreds of other proteins—known collectively as interferon-stimulated genes (ISGs)—that have roles in combating viruses and other actions produced by interferon.[13][14] They also limit viral spread by increasing p53 activity, which kills virus-infected cells by promoting apoptosis.[15][16] The effect of IFN on p53 is also linked to its protective role against certain cancers.[15]

Another function of interferons is to up-regulate major histocompatibility complex molecules, MHC I and MHC II, and increase immunoproteasome activity. All interferons significantly enhance the presentation of MHC I dependent antigens. Interferon gamma (IFN-gamma) also significantly stimulates the MHC II-dependent presentation of antigens. Higher MHC I expression increases presentation of viral and abnormal peptides from cancer cells to cytotoxic T cells, while the immunoproteasome processes these peptides for loading onto the MHC I molecule, thereby increasing the recognition and killing of infected or malignant cells. Higher MHC II expression increases presentation of these peptides to helper T cells; these cells release cytokines (such as more interferons and interleukins, among others) that signal to and co-ordinate the activity of other immune cells.[17][18][19]

Epstein–Barr virus lytic reactivation (which can be due to chemotherapy or radiation) can result in genome instability and cancer.[5]

HSV reactivates upon even minor chromatin loosening with stress,[7] although the chromatin compacts (becomes latent) upon oxygen and nutrient deprivation.[8]

Cytomegalovirus (CMV) establishes latency in myeloid progenitor cells, and is reactivated by inflammation.[9] Immunosuppression and critical illness (sepsis in particular) often results in CMV reactivation.[10] CMV reactivation is commonly seen in patients with severe colitis.[11]

viral latency is so fucked up

[fuhdubai]

MEN'S HEALTH AWARENESS MONTH

The 'Movember' campaign takes place every November, to raise awareness and funds for men's mental health, suicide prevention, prostate cancer and testicular cancer.

‍ To mark the awareness month, experts from Fakeeh University Hospital share advice on what men in the UAE need to start doing to boost their health and live their best life     

IT’S TIME TO ‘MAN UP’ AND TAKE CHARGE OF YOUR HEALTH

If you’re a man in your 30s or older, seeing a doctor or getting a checkup is most likely the last thing on your mind when you have a million other things to worry about. But, if recent data is anything to go by, it is the most critical thing you can do.      

According to the latest figures from SEHA, men in the UAE are not doing enough to take charge of their health. 70 percent of Emirati men under the age of 30 years are known to suffer from obesity and diabetes[1]. Not enough men between 20 to 30 years of age are undergoing regular full physical work-ups, and screening for prevalent health issues.   

In recognition of Men’s Health Month, the message is clear: men (young and old) need to take charge of their own health by proactively learning where their health is at and preemptively seeking treatment and guidance. To mark the occasion, experts across multiple specialties at Fakeeh University Hospital share their advice on the best place to start.   

WHEN / WHY A UROLOGIST SHOULD BE PART OF YOUR LIFE

As men enter their 30s and later, quality-of-life issues become more pertinent, requiring early action to monitor and detect any urology issues. They may resist at first, especially if they need to be dragged to their primary care physician for annual checkups but seeing a urologist can make everyday life better.      

Dr. Hosam Al Qudah, Consultant and Lead Urologist Fakeeh University Hospital believes that starting an open dialogue with a urologist is key to addressing the problems men often do not feel comfortable discussing: “I recommend every man over the age of 40 to start seeing a urologist regularly. This isn’t just something you do to protect yourself from prostate cancer. This is about taking charge of your prostate, urinary, and sexual health – to talk about the issues that you may find uncomfortable to address. This is also where I see our role as urologists – to normalize these as regular health conversations”.   

In their late 40s, men may begin to face difficulty urinating due to an enlarged prostate, which is part of getting older. But too many trips to the bathroom — day and night — can make daily life more of a pain than it needs to be. To start, a urologist may recommend some lifestyle changes. This can include avoiding caffeine and alcohol. An enlarged prostate can also be treated with medications to relieve symptoms or even partially shrink the prostate.   

The greatest concern here is the lifetime risk of prostate cancer, which can be predicted by a single prostate-specific antigen (PSA) determination that men are recommended to take during their 40s. “All men should take a baseline PSA test when they hit their mid-40s,” says Dr. Hosam. “It’s a simple blood test can help determine your risk of developing prostate cancer and show us specifically what we need to do to screen you in the future.”   

If your PSA is .7 or below, you may only need to be screened every five years or so and your lifetime risk of prostate cancer is around 10% or less. If you’re at higher risk with a score of 1 or above, you may benefit from more frequent screening. If you reach 60 and your score is below a 1 or 2, it is safe to spread out the screening interval again. “Cancer screenings can be lifesavers,” continued Dr. Hosam, “but even a semi-regular visit to your urologist can keep you feeling good and make the aging problems all of us men face a little easier to cope with.”   

Erectile dysfunction and declining libido are other issues that are not uncommon for men starting in their late 40s and early 50s, with about 1 in 10 adult males suffering from it[1]. The cause isn’t always physical, but a urologist can help if it is. “Your urologist can check your hormones with a simple blood test and prescribe testosterone replacements if you have low testosterone,” said Dr. Hosam.   

[myrawjcsmicasereports]

Covid-19 associated autoimmune encephalitis in Iraq. A Case Report by Faiq B. Basa in Journal of Clinical Case Reports Medical Images and Health Sciences

Abstract

Covid-19 infection frequently causes neurological symptoms. One of the mechanisms of indirect nervous system involvement is through inflammatory response and immune dysregulation. There are few recorded cases of indirect involvement of CNS by auto-antibodies. We present a case of a 6-year-old Iraqi boy with anti–N-methyl-d-aspartate receptor (anti-NMDAR) autoimmune encephalitis, associated with Covid-19. He presented with recent repeated attacks of refractory focal seizures preceded by behavioral changes. Serum and CSF anti-NMDAR antibodies were positive. Early recognition and treatment of autoimmune encephalitis are crucial as the prognosis is promising with early immunotherapy. Autoimmune encephalitis should be included in the main differential diagnosis whenever refractory epilepsy or new onset status epilepticus is faced. In the era of COVID-19, high vigilance is required as a possible association may increase autoimmune encephalitis incidence.

Key Words: Autoimmune encephalitis, Covid-19, refractory seizures, Anti-NMDA receptor encephalitis.

Introduction

The new coronavirus disease (Covid-19) was initially detected in Wuhan, China, in December 2019 [1]. There are now established Covid-19 cases with neurological symptoms, which developed either through direct harm of the central nervous system (CNS) caused by the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), or via autoimmune processes [2, 3]. Several neurological complications have been described: encephalitis, meningitis, cerebrovascular diseases, acute disseminated encephalomyelitis (ADEM), and encephalopathies [4, 5].

Encephalitis is an inflammatory condition affecting the brain. Its etiologies are diverse. There are two main types of immune mediated encephalitis: (1) the paraneoplastic encephalitis syndromes, often associated with antibodies against intracellular neuronal proteins (onconeuronal proteins) [6]; (2) encephalitis syndromes associated with antibodies against neuronal cell surface/synaptic proteins, known as autoimmune encephalitis (AE) [7]. While paraneoplastic encephalitis syndromes are invariably cancer-related, autoimmune encephalitis syndromes may occur in the presence or absence of cancer.

AE includes a spectrum of disorders depending on the type of autoantibodies that are directed against various receptors and synaptic receptors and channels. The most common type of AE is the anti–N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis, which was first described by Dalmau and colleagues in 2008 [8].

More recently, many new antibodies targeting neuronal surface antigens and synaptic proteins causing different forms of AE have been discovered, including those caused by autoantibodies targeting GABAB-R, GABAA-R, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), and contactin associated protein-like 2 (CASPR2), leucine-rich glioma inactivated 1 (LGI1), dipeptidyl-peptidase-like protein 6 (DPPX), Ig LON5, and others [9]. Additionally, AE might be the diagnosis behind new onset refractory seizure or status (NORSE), atypical movement disorders, rapidly progressive dementia of unknown etiology, or psychiatric and behavioral disturbances, sometimes mistaken for primary psychiatric illnesses [10].

In addition to the established association of AE with tumors like, e.g., ovarian teratoma in anti-NMDAR encephalitis, also the possibility of an association with SARS-CoV-2 infection arose. At present, there are few reported cases with positive anti-NMDAR encephalitis in association with COVID-19 [11, 12]. Nevertheless, this possible association will need more attention when neurologists, psychiatrists, and physicians face cases of unexplained refractory seizure and/or psychiatric manifestation.

Here, we report a unique case of a 6-year-old boy who presented with repeated attacks of refractory focal seizures, associated with autoimmune encephalitis.

Case Report Presentation

The parents of a 6-year-old boy from Erbil, Iraq, with normal perinatal and developmental history and no other known medical illnesses noticed an unusual decreased physical and cognitive activity, as new-emerging eating disorders. After a few days, while sleeping, the child developed abnormal body movements restricted to the left face and left body side with impaired consciousness. Therefore, he was taken to a pediatric emergency department.

After admission, the focal seizures, altered consciousness, and fever continued for two weeks. Consequently, he had to be intubated for 5 days in a Respiratory Care Unit (RCU), from which he was discharged after the seizures became less frequent. As per clinical findings, the patient was drowsy and mute, he had orofacial dyskinesia, and spastic quadriparesis, with infrequent focal seizures.

A brain MRI showed bilateral deep white matter cerebral hemisphere increased T2/FLAIR signal . EEG detected diffuse slowing and abnormal epileptic discharge .

Cerebrospinal Fluid (CSF) was clear and colorless. CSF glucose level was 55.7 mg/dL, and CSF total protein 14.6 mg/dL. No abnormal cells were detected. CSF oligoclonal bands (OCB) were positive. Real-time polymerase chain reaction (RT-PCR) assay was positive for severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2). Central Nervous System (CNS) tuberculosis and Viral Encephalitis were excluded by Cerebrospinal fluid polymerase chain reaction (CSF-PCR) assays. Serum and CSF anti-NMDA receptor IgG Ab were positive.

The therapeutic intervention started with intravenous (IV) methylprednisolone therapy (15 mg/kg/day) for 5 days, followed by intravenous immunoglobulin (IVIG), according to the high-dose immunomodulatory therapy strategy (1,000 mg/kg), for 5 days [13]. Anti-seizure medication (ASM) was commenced as well.

In the following weeks a mild improvement in terms of enhanced consciousness, limbs movements, and weight gain was observed. Therefore, the nasogastric tube was removed, and oral feeding restarted. We monitored the child through regular evaluations and biochemical analyses until complete clinical recovery. ASM was not discontinued. The overall treatment was well tolerated.

Discussion

Autoimmune encephalitis is a condition that can be easily missed as it is not commonly considered in the differential diagnosis of various medical presentations. However, such diagnosis should be always taken into consideration when a person, particularly a child, presents with a new onset of refractory status epilepticus (NORSE) and/or new behavioral or psychiatric conditions. An early diagnosis of AE is essential, as the treatment is different from other conditions. With correct timely interventions the outcome is frequently favorable.

Though SARS-Cov-2 virus rarely invades the nervous system, Covid-19 infection frequently causes neurological symptoms like headache, delirium, anosmia, and dysgeusia [14]. One of the mechanisms of indirect nervous system involvement is through inflammatory response and immune dysregulation. There are few recorded cases of indirect involvement of CNS by auto-antibodies that are directed against the surface and synaptic protein. This case is one of the rare cases of Anti NMDA antibody autoimmune encephalitis that is associated with Covid-19 infection [15]. It indicates that in the era of COVID-19, high vigilance is required as a possible association may increase AE incidence.

A recent systemic review that analyzed 16 studies, including a total of 161 patients with NORSE [16], showed that the most frequent cause was AE. In addition to the well-known association with teratoma and cancer, AE, and specifically Anti-NMDA receptor Ab encephalitis, could be associated with a SARS‑CoV‑2 infection, either concomitantly or as post-infection manifestation. In this reported case, immunotherapy, in addition to anti-seizure medication, showed to be effective.

The main limitation of this report is the relatively short follow-up period. Observation of the child is ongoing to detect possible medium- or long-term consequences.

Conclusion

This case demonstrated that autoimmune encephalitis should be always considered when facing a new onset of refractory epilepsy and/or abnormal behaviors, and that it could be associated with SARS-Cov2 infection. Early diagnosis of an autoimmune encephalitis and ensuing correct treatment can be lifesaving.

Statement of Ethics: The parents of the child involved in this study have given their written informed consent to publish his case (including the publication of images). Ethical approval is not required for this study in accordance with national guidelines.

Conflict of Interest Statement: The authors have no conflicts of interest to declare.

Funding Sources: This case report required no funding.

[twinkl22004]

“Kappa Light Chain Deficiency”, Victor McKusick, Mendelian Inheritance in Man, 1966. 卡帕轻链缺陷。(IGKC).

Here I present: “Kappa Light Chain Deficiency”, Victor McKusick, Mendelian Inheritance in Man’, 1966. 卡帕轻链缺陷。(IGKC). INTRODUCTION. Immunoglobulins are the antigen recognition molecules of B cells. The immunoglobulin light chain is the small polypeptide subunit of the antibody (immunoglobulin).  A typical antibody is composed of two (2) immunoglobulin heavy chains and two (2) immunoglobulin…

[didanawisgi]

 On activation of the downstream signaling, the body will recognize and responds to viral RNAs. This recognition of single and double-stranded RNA is by endosomal receptors such as Toll-like receptors (TLR3), TLR7, and TLR8. Double-stranded and 5′-triphosphate modified RNA is recognized by the cytosolic receptor’s retinoic acid-inducible gene-I (RIG-1) and melanoma differentiation-associated protein 5 (MDA-5). Allergic reactions and anaphylactic shock were reported when the body’s immune system is activated in an uncontrolled manner. This overstimulation of the immune system on a molecular level will limit the protein translation, expression of antigens, and vaccine efficacy. This limitation can be overcome by nucleobase modifications. N1-methylpseudouridin, a modified nucleobase, will increase the protein output and decrease the activation of TLR3. Modified nucleotides through RIG-1 not only affect protein-RNA interaction but also decrease the ability of mRNAs to disseminate immunological signals. Translation efficiency of mRNA into protein is improved because of N1-methylpseudouridin.

[a-typical]

What’s the difference between Pfizer/BioNTech, Moderna, and Novavax COVID-19 vaccines?

The Pfizer-BioNTech and Moderna COVID-19 vaccines use mRNA as the active ingredient. The mRNA is converted by our cells into the antigen, in this case, the spike protein of SARS-CoV-2.

The vaccine contains the mRNA, which is synthesized in the lab using a DNA template, the building blocks of RNA, and the enzyme that puts those building blocks together into the right order. mRNA is the molecule template for every protein in every organism. The mRNA sequence is a code for our cells to link amino acids together into functional proteins

mRNA is very fragile, so it is encased in a lipid nanoparticle (LNP) that protects it until it gets into our cells. When the vaccine is administered, the mRNA is released and is used to synthesize the spike protein which is displayed by cells that produced it. That spike protein is recognized by our innate immune cells like dendritic cells and macrophages as well as B cells, which initiates immune response and generation of memory immunity.

In contrast, Novavax is a protein-based vaccine, which contains the prefabricated antigen - the spike protein - instead of the template for it. To make the antigen, we turn cells into protein-producing factories in the lab.

Novavax uses Sf9 cells (moth cells) infected with an insect-specific virus that has been genetically engineered to contain the gene for the spike protein of SARS-CoV-2. These viruses will hijack the cellular machinery of the Sf9 cells to produce lots of spike proteins and baby viruses. Those will continue to reproduce and produce proteins, which will be harvested, purified, and formulated with the other ingredients in the final vaccine.

When the vaccine is injected, the antigen will be recognized by the same innate immune cells listed above, which will trigger the same immune response pathway.

While the vaccines use different technologies, ingredients, and manufacturing processes, the immune responses center around recognition of the spike protein and generating adaptive immune responses targeting that antigen.

[evoldir]

Fwd: Graduate position: UHamburg_Germany.EvolutionaryGeneticsImmunity

Begin forwarded message: > From: evoldir@evol.biology.mcmaster.ca > Subject: Graduate position: UHamburg_Germany.EvolutionaryGeneticsImmunity > Date: 4 August 2024 at 05:11:01 BST > To: rdmpage@gmail.com > > > > We invite applications for a PhD position to study the evolution, > genetics and genomics of the adaptive immune system (especially > MHC/HLA), using humans and/or fish as a model system. The specific topic > is open and will be matched with the candidate's interests and skills. > We use both computational and molecular approaches in our lab. > > The position is a full-time PhD position funded for initially 3 years. > In Germany, PhD students are expected to complete their PhD work within > three years, as they don't have to collect course credits. However, > extensions are possible depending on funding availability. A Masters > degree in a relevant field is required to apply. > > *The application deadline is August 25* > > Please follow this link to apply online through the university system: > > https://ift.tt/Cqp2X9B > > In our group we are studying the genetic basis for variation in > immunocompetence and disease susceptibility in vertebrates, with a > particular focus on the adaptive immune system and specifically the > process of antigen presentation (MHC/HLA) and recognition (TCR/T cell > repertoires). Our main model systems are humans and three-spined > sticklebacks (a small, but cool fish). We usually take an evolutionary > perspective and aim to understand the factors and mechanisms that > maintain genetic diversity in the context of host-pathogen coevolution > (in both humans and fish), but we are also interested in the > consequences of this diversity for the individual's health and have > several ongoing collaborations with clinical groups on specific complex > diseases in humans (e.g. HIV, Tuberculosis, autoimmunity, cancer). > Several project ideas are available in this context and can be tailored > to the candidate’s interest and experience. > > We expect the successful candidate to have a decent background in > molecular and evolutionary biology. Some knowledge of immunology and > bioinformatics would be a plus. For more specific requirements and > duties, including a minor level of teaching, please see the advert link > above. We offer an inspiring research environment with expertise in > molecular, evolutionary, and computational biology, immunology and > population genetics/genomics. Our group has state-of-the art molecular > labs, including NGS sequencing capacity, and has priority access to the > university's HPC cluster. > > Our newly renovated labs and offices in the Institute for Animal Cell > and Systems Biology at the University of Hamburg are situated in the > middle of Hamburg, the second largest city in Germany. The institute is > neighboring the main university campus with its bustling student life > and cafes, and is easy to reach by bike or any public transport (and > car, if you must). > > Please see also our lab website for more info: > https://ift.tt/WEJAeBN > > Please do not hesitate to contact me for informal inquiries, > Tobias Lenz > > > > Prof. Dr. Tobias Lenz, Heisenberg-Professor > Research Unit for Evolutionary Immunogenomics > University of Hamburg > Department of Biology > Institute of Animal Cell and Systems Biology > Martin-Luther-King-Platz 3 > 20146 Hamburg, Germany > > Email: tobias.lenz@uni-hamburg.de > > https://ift.tt/WEJAeBN > > > > tobias.lenz@uni-hamburg.de > > (to subscribe/unsubscribe the EvolDir send mail to > golding@mcmaster.ca

[maryjayne1]

Questions and Answers

We’ll secure this post at the top and gradually incorporate your inquiries, providing answers alongside. Please ask any questions in the comments section below. This approach will streamline the search process. Let’s initiate this process with:

This approach will help me with questions and answers frequently asked:.

_________

1. What is the main purpose of gcmaf.

GcMAF is an immunotherapy product that, according to current clinical experiences, has been free of any adverse side effects in patients. It is designed to activate macrophages, which are crucial components of the immune system.

2. What does GcMAF stand for, and what rolls does it play in our bodies?

GLYCOPROTEIN MACROPHAGE ACTIVATING FACTOR

Lets Explore Gc Proteins, followed by their separate role in the Macrophage Activation factor.

A glycoprotein is a class of proteins that have carbohydrate groups attached to their polypeptide chains. This attachment of carbohydrates, known as glycosylation, occurs during or after the protein is made (cotranslational or posttranslational modification). Glycoproteins are found throughout the body and play various roles, including in cell structure, immunity, hormones, and cell-cell interactions . They are also integral to the membranes of cells, where they are involved in signaling and recognition processes. Glycoproteins can be categorized by their glycosylation type, such as N-linked or O-linked, depending on where the sugars are attached to the amino acid chain .

MAF: Macrophage-activating factor (MAF) is a type of signal, often a lymphokine, that primes macrophages to become more active in various immune functions. This includes enhancing their ability to destroy tumor cells, secrete cytokines, and clear pathogens . MAFs also influence macrophages to present antigens via MHC I molecules, participate in T-helper (Th) cell responses, and affect other immune responses.

Macrophages can exhibit different activated phenotypes depending on the combination of MAFs they receive. These are primed by signals like IFNγ and TNF to have increased activity against pathogens and tumor cells, and they secrete inflammatory cytokines.

Regulatory macrophages: These are induced by factors like glucocorticoids and are involved in producing anti-inflammatory cytokines like Interleukin 10, which can inhibit immune responses.Overall, MAFs play a crucial role in determining the behavior and function of macrophages within the immune system.

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3. Does GcMAF have the ability to reduce inflammation?

We have studied GcMAF for its potential role in modulating the immune system, which includes the ability to reduce inflammation.

This research suggests that GcMAF helps regulate the body’s inflammatory response by activating macrophages at sites of infection or inflammation and then inducing their apoptosis, which is the process of programmed cell death, when they are no longer needed. This, according to scientific findings, helps reduce the severity and duration of inflammatory responses.

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4. What are the ingredients of the polar GcMAF sprays and vials that you discuss within this group.

Deglycosylated GC MAF in stablised PBS buffer system.

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5. What time of day is best to use the spray and is with or without food and water.

Based on current guidelines, it’s advised to take first thing in the morning and refrain from consuming any food or drinks for 15 minutes prior to and following the use of the spray. The dosage varies depending on the purpose of usage and the age of the individual, with lower amounts recommended for children.

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6. Is GcMAF useful for horses and pets.

Please understand that medical trials are conducted on animals for several key reasons, which are for humans and pets. Jump to number 5 if you are overwhelmed with my response

:

Animals, particularly mammals like mice, share a significant amount of their DNA with humans, making them suitable models for studying human diseases and treatments https://med.stanford.edu/animalresearch/why-animal-research.https://www.bing.com/search?form=SKPBOT&q=Biological%20Similarity

1. : Animals can develop many of the same health issues as humans, such as cancer, diabetes, and heart disease, allowing researchers to study these conditions and potential treatments https://med.stanford.edu/animalr.../why-animal-research.html.

And https://www.bing.com/search?form=SKPBOT&q=Health%20Problem%20Susceptibility

2. : With shorter life cycles, animals can be observed over their entire lifespan or even across generations, providing valuable insights into disease processes and long-term effects of treatments https://med.stanford.edu/animalr.../why-animal-research.html. And https://www.bing.com/search?form=SKPBOT&q=Whole%20Life%20Span%20Study

3. : It’s often not feasible or ethical to perform certain types of research directly on humans, so animals serve as surrogates to test the safety and efficacy of new treatments before they are considered for human trials https://med.stanford.edu/animalr.../why-animal-research.html.

And

4. : Many treatments developed for human use are also beneficial for animals, improving veterinary care and contributing to the health of pets https://med.stanford.edu/animalr.../why-animal-research.html

And https://www.bing.com/search?form=SKPBOT&q=Veterinary%20Benefits

The results from animal trials are crucial for advancing medical science, but it’s important to note that they don’t always directly translate to humans due to species differences. What works in animals may not work the same way in humans, and vice versa. Therefore, while animal studies provide a foundation, they are just one step in a comprehensive process that includes rigorous human clinical trials to ensure safety and effectiveness for human patients https://medicalxpress.com/.../2017-08-animal-trial....

5. In the context of pets, most of the findings from animal trials can be applicable, as many pets are also mammals and share similar biological systems. However, each species has its unique characteristics, so veterinary scientists must carefully evaluate how findings from one species can be applied to another. This is why the development of veterinary medicines also involves specific trials designed for the target species https://med.stanford.edu/animalr.../why-animal-research.html.

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6. According to research. Would GcMAF be useful for PANS/PANDA

pediatric acute-onset neuropsychiatric syndrome is commonly called PANS. PANDAS is a subtype of PANS with a specific known cause, exposure to a strep infection. While PANS/PANDAS occurs mostly in children who do not also have Autism Spectrum Disorder, in rare cases, a child may have both conditions.

PANS is an infection-triggered autoimmune disorder affecting the basal ganglia, which can result in a multitude of neuropsychiatric symptoms, including OCD-like behaviors, tics and/or restrictive eating in children and adolescents.

Because it is an autoimmune condition, and this will cause inflammation and nagalase levels to spike. In accordance with science studies, yes, Gcmaf has the capacity to benefit PANS patients. It is not claimed as a curative approach. Gcmaf has the ability to help the immune system as described in the scientific research provided in this group.

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7. Is GcMAF in food?

While some products claim to contain or stimulate the production of GcMAF, these claims are not supported by scientific evidence. It’s important to be cautious of claims regarding GcMAF in food products and to rely on peer-reviewed scientific research when considering health-related information.

Milk products are not considered GcMAF for several reasons:

1. GcMAF is a specific protein derived from the modification of vitamin D-binding protein, which is not naturally present in milk products such as yogurt.

2. Milk products do not contain GcMAF and therefore can not be claimed to have the same purported benefits

3. It’s important to differentiate between naturally occurring compounds in milk and those that are the result of specific scientific processes, like the production of GcMAF. Milk products, while nutritious, do not contain GcMAF and should not be confused with it or its associated medical claims.

GcMAF (Gc protein-derived macrophage-activating factor) is a naturally occurring protein in the human body that plays a role in the immune system. It is not typically found in foods. Instead, GcMAF is a result of the modification of vitamin D-binding protein, which is a process that does not occur in food production or preparation

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8. Where can I purchase Gcmaf and what is the product range?

I don’t sell any products, I study the science.

I am often asked what countries have distributorships for the GcMAF, which we refer to and what is the range of products. The range of products are as follows:

Nasal and mouth sprays 7500ng in 20ml units

Nasal and mouth sprays 1500ng in 20ml units

Vials 7500ng in 3ml units

Vials 1500ng in 3ml units

Creams 15,000ng in 40ml units

Currently these are the countries with distributorships:

America

Europe

Isreal

Turkey

England

Candice Bradstreet is in contact with all distributors, she will connect you with your nearest distributor. she can be contacted in this group or, you can private message me for details, or even email me ariamaryjayne@gmail.com

if emailing, please check your spam folder within 48 hours, if you have not received my reply.

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9. What are your thoughts regarding GcMaf plus creams.

I prefer to base my response through science.

The product in question is derived from raw bovine colostrum and undergoes a fermentation process. It is important to note that fermentation will initiate the degradation of GcMAF. Furthermore, the pH balance and composition of this cream, which includes both antioxidative and antioxidant elements, appear to lack harmonious integration. The inclusion of vitamins in topical formulations may not be beneficial unless a deficiency exists. Due to the nuances of its manufacturing process, the cream cannot be classified as a GcMAF product. While this does not negate other potential utility of the cream, it is crucial to understand that the final product doesn’t align with its purported claims. My expertise is centered on the study of GcMAF products exclusively.

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10. Can GcMAF be made at home? The ingredients of genuine gcmaf are not YOGURT they are as follows; Deglycosylated GC MAF in stablised PBS buffer system.

This group refers to Gcmaf which CAN NOT be made from fermentation, spores or yogurt culture. You are forming a probiotic which is NOT gcmaf. Gcmaf is a complex process that CAN NOT be made at home in a kitchen. Deglycosylation process and buffer system is only part of the technology of gcmaf. There are two interpretations for the fermentation. One is, using any industrial enzyme to produce products so fermentation here referes to enzyme activity. But, in biochemical terms fermentation is a different pathway of cell metabolism which is followed by glycolysis.

Yogurt making at home IS NOT GCMAF!

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11. Does Gcmaf cure Autism?

Cure is a big claim which I can not make.

There are too many co-factors when it comes to the Autism umbrella.

After reading study cases and observing results. I see the benefits for individuals on the Autism spectrum with elevated nagalase levels. I have whitnessed gcmaf aiding in speech development, coordination, and other life skills. I recall detailing a specific case study involving a young individual whose progress I closely monitored, it was shared within this group. The comprehensive analysis revealed significant improvements: enhanced speech, increased calmness, reduced repetitive behaviors, better coordination, and responsive behavior to parental instructions. Notably, the individual named Wes, began to exhibit empathy and initiate affectionate gestures like hugs, there were other positive changes observed which you can read about.

Together with Dietary enhancements, tailored to address deficiencies identified in blood tests, also contributed to the overall progress.

While this product is not a cure for autism — a condition with diverse etiologies including genetic factors, environmental influences, and in some cases vaccine-related impacts — it can be a valuable component of a broader therapeutic strategy.

In summery, the product has no known side effects, if nagalase levels are high, it certainly has the potential to make a difference. I don’t see it as a fully curable measure.

It’s important to recognize that autism has multifaceted origins and would seem to support a holistic approach to management.

Reference link to Wes, the case I followed and recorded:

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12. What’s is the difference between the applications of creams, vials and sprays:

Transdermal applications, such as the creams, are meticulously formulated to match the skin’s pH and optimize penetration. The skin’s outermost layer, the stratum corneum, acts as a barrier but has been traversed by science through various mechanisms, including hydration of the skin, which alters the barrier properties, and the use of chemical enhancers that modify the lipid structure of the stratum corneum to increase its permeability. This method is recorded particularly beneficial for children who may not tolerate sprays and for targeting skin conditions while also providing systemic immune support.

Nasal sprays are absorbed through the mucosa in the nasal cavity, which is richly vascularized, allowing for rapid systemic absorption and bypassing first-pass metabolism. This route is advantageous for delivering the active ingredients swiftly to the bloodstream, producing a quick therapeutic effect. while also providing systemic immune support.

Sublingual administration:

This is where the spray is placed under the tongue, is another effective absorption route due to the rich blood supply in that area.while also providing systemic immune support.

Injectable is often the preferred method for more severe conditions due to their high absorption rates and rapid onset of action. Subcutaneous injections injections deliver Gcmaf directly and absorbed slowly which seems to showing favorable results in the treatment of certain Cancer, giving a gradual release into the bloodstream .In summary, the choice of delivery method — transdermal, nasal, or injectable — depends on the condition being treated, the desired speed of absorption, and patient-specific considerations.

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13. Hi i have the order form! it has Oral Colostrum

VDTP tablets

60 pills per unit. I’m interested to know what these do? Compared to spray ect.

I have previously discussed how colostrum products should be avoided.

I advise against the consumption of milk-based products during serious illness, including colostrum. Lactose, the sugar found in milk derived products, are more difficult for individuals to digest, especially when they are unwell. This is because the body may produce less lactase, the enzyme needed to break down lactose, leading to discomfort such as bloating, gas, and diarrhea. Moreover, dairy is well known to thicken mucus, which might exacerbate symptoms. Therefore, avoiding lactose can help prevent these potential issues and contribute to a more comfortable recovery.

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14. Is GcMAF legal?

Gcmaf is currently considered off-label, which doesn’t means it’s illegal. In situations involving late-stage cancer, where no alternative curative treatments are available, off-label products may be considered by people. Health is not owned by the FDA!

Products not approved by the FDA are not illegal; it simply indicates that they have not been verified by the FDA for specific uses.The FDA is a private company.

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15. My child doesn’t like nasal sprays and it is difficult to get the spray under his tongue, please advise.

Please don’t be concerned regarding the absorption of gcmaf orally as absorption in the mouth occurs not only only sublingual but also using buccal routes. Sublingual administration involves administration under the tongue where it dissolves and is absorbed by the blood vessels there. This method allows the medication to enter the bloodstream quickly, bypassing the digestive system.Buccal administration is when the drug is placed between the gums and the cheek. The medication dissolves and is absorbed by the blood vessels in the cheek.Both methods are used for their rapid absorption into the bloodstream and are beneficial for patients who may have trouble with the nasal spray.

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16. Is D3 important:

Hormone/vitamin D3 is directly connected to Gcmaf.

There are limitations of the D25 test known as 25 hydroxy, the D25 test only measures vitamin D’s inactive form and might not fully reflect one’s vitamin D levels due to individual differences in how it’s converted to the active form, D1,25, influenced by genetic factors.

It’s advisable not to depend solely on the D25 test for assessing vitamin D levels.

This test, which measures the inactive form of vitamin D, hasn’t been updated to reflect our current understanding of vitamin D metabolism.

The test operates on the outdated belief that everyone converts inactive vitamin D to its active form at the same rate. However, genetic research has revealed that this conversion rate varies significantly among individuals due to differences in their vitamin D receptor (VDR) genetics. Consequently, a person who converts vitamin D slowly may appear to have adequate levels when, in fact, their active vitamin D level is low. Conversely, a fast converter might show low D25 levels but could actually have high active vitamin D levels, risking toxicity if given additional synthetic vitamin D.

It’s challenging to find doctors skilled in interpreting these tests by their ratio. For a safer assessment, it’s recommended to measure both D25 and active D1,25 levels from the same blood sample.

Acknowledging that the conversion from inactive to active vitamin D varies among individuals is crucial for accurate vitamin D assessment. Genetic differences affecting the vitamin D receptor (VDR) play a significant role in this process and consequently, in the body’s response to vitamin D intake.

Measuring both D25 and D1,25 levels simultaneously offers a more complete picture of vitamin D status and metabolism.

This dual measurement can reveal the balance between the vitamin D forms, informing more tailored supplementation plans. We recommend to measure both D25 and D1,25 levels for a comprehensive evaluation and to account for individual metabolic variations.

The metabolic pathways of Vitamin D are complex, with each form serving distinct functions. The key lies in maintaining a balance among all these components for optimal results.

The impact of synthetic substances, including d3 on retinol uptake, can vary depending on the specific context and the synthetic compounds in question. Generally, retinol uptake into cells is facilitated by certain proteins, such as stimulated by retinoic acid 6 (STRA6). In some cases, alterations in the expression of these proteins can affect retinol uptake. For instance, a study on endometriosis showed that progesterone receptor is necessary for high STRA6 expression, which controls retinol uptake. In endometriotic stromal cells, decreased expression of STRA6 led to reduced retinol uptake.

D3

It is possible to produce non-synthetic vitamin D3. Natural sources of vitamin D3 include lichen, a type of algae that grows on rocks and tree bark, and is a sustainable source of vitamin D3 https://organicshortlist.com/organic-vitamin-d/. Vitamin D3 can also be derived from fish oil and sheep lanolin. Fish oil comes from the skin of fatty fish such as salmon or tuna, which naturally contain vitamin D, while lanolin is a waxy substance secreted by glands found in a sheep’s skin

Moreover, advancements in technology have led to the development of methods like the continuous microflow process, which is a greener and more efficient way to synthesize vitamin D3 compared to traditional batch processes

This process involves UV photoirradiation and high temperature and pressure to optimize and simplify the synthesis of crystalline vitamin D3 https://link.springer.com/article/10.1007/s11367-019-01634-6.

It’s important to note that when choosing vitamin D supplements, it’s beneficial to look for those that are labeled as natural or organic, as they are likely to be free from synthetic additives and may be better for health and safety https://www.approachwellness.com/natural-vitamin-d.html.

Please take a 25 hydroxy test to establish your D3 levels, 90 to 100 is the optimal range to aim for.

Here are some links to purchase a good source of D3. Feel free to add other plant forms in the comments section of this post.

UK https://www.british-supplements.net/.../clean-vitamin-d3...

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17. Does Gcmaf activate vitamin D receptors?

GcMAF itself does not directly activate vitamin D receptors (VDR), it is involved in the pathway of vitamin D metabolism. The activation of macrophages by GcMAF can lead to various downstream effects, including those related to vitamin D functions. For instance, the activation of VDR modulates the expression of certain cytokines which are responsible for a shift toward the M1 phenotype of macrophages.In summary, GcMAF is closely related to the vitamin D system and its effects on the immune system, but it does not directly activate vitamin D receptors. Instead, it influences the immune response through its action on macrophages and is associated with the broader regulatory mechanisms of vitamin D.

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28. Are herxheimer/ detox reactions ever a side effect when starting sublingual GcMAF? Thank you.

During the 24 years of research no known negative side effects have been reported.

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29. Where can I purchase nagalase kits.

Nagalase kits can be purchased online. Note: change the currency to usd by clicking on the price

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30.

3

Only questions relating to GcMAF. Other health related topics can be found in other groups we manage

And

#maryjaynearia #glycoproteins #gcmaf #D3

Only questions relating to GcMAF. Other health related topics can be found in other groups we manage

And

#maryjaynearia #glycoproteins #gcmaf

[casestudies-crimson]

Allogeneic Chimeric Antigen Receptor T Cells: A Further Potential Weapon for Haematological Malignancies_Crimson Publishers

Autologous (patient-derived) Chimeric Antigen Receptor T (CAR T) cells have widely proven their efficacy to treat certain B-cell haematological malignancies [1-3]. However, autologous CAR-T presented some limitations regarding both the manufacturing process and the use of T cell exhaust due to several therapy lines [4,5]. The possibility to use cells from healthy donors, referred to as “off-the-shelf” allogeneic CAR T or universal CAR T (UCART) could potentially overcome these limitations, as well as making a marked reduction in costs due to the implementation of industrialized manufacturing process. At the same time, the creation of batches allowed the possibility to have a product immediately available also for redosing, if necessary. However, allogeneic approaches are associated with two major issues: the life-threatening Graft Versus Host Disease (GVHD) and the short persistence of allogeneic CAR-T due to host immune recognition. Here, we report the promising results of the main phase-1 clinical trials in haematological malignancies [6].

Read More About this Article: https://crimsonpublishers.com/aics/fulltext/AICS.000576.php

Read More Articles: https://crimsonpublishers.com/aics/

[mblinternationalcorporation]

Non-Classical MHC Tetramers in Health and Disease: Emerging Trends

Major Histocompatibility Complex (MHC) molecules are essential components of the immune system, playing a crucial role in antigen presentation and immune response. Traditionally, research has focused on classical MHC molecules (MHC class I and II). However, recent advances have highlighted the significance of non-classical MHC molecules, specifically non-classical MHC tetramers, in health and disease. These molecules have distinct structural and functional properties that differentiate them from their classical counterparts, offering new insights and therapeutic possibilities in immunology.

Understanding Non-Classical MHC Molecules

Non-classical MHC molecules, including HLA-E, HLA-F, HLA-G in humans, and their murine equivalents (Qa-1, Qa-2, and others), exhibit limited polymorphism compared to classical MHC molecules. They are expressed in specific tissues and have unique roles in immune regulation, such as tolerance induction and modulation of immune responses. Non-classical MHC molecules present a broader range of antigens, including non-peptidic antigens, lipids, and small molecules, to specialized subsets of T cells and natural killer (NK) cells.

Structure and Function of Non-Classical MHC Tetramers

Non-classical MHC tetramers are complexed structures composed of four MHC molecules bound to specific antigens, forming a tetramer that can be used to stain antigen-specific T cells. These tetramers are valuable tools for studying the immune response, allowing researchers to track and characterize antigen-specific T cells with high precision. Unlike classical MHC tetramers, non-classical MHC tetramers often interact with non-peptidic antigens and can engage with both T cell receptors (TCRs) and NK cell receptors, broadening their functional scope.

Antigen Presentation

One of the primary functions of non-classical MHC tetramers is to present antigens to T cells and NK cells. For instance, HLA-E tetramers present peptides derived from the leader sequences of other MHC class I molecules, interacting with the CD94/NKG2 receptor on NK cells and some T cells. This interaction plays a crucial role in immune surveillance and the regulation of NK cell activity, contributing to the recognition of infected or transformed cells.

Immune Regulation

Non-classical MHC tetramers also contribute to immune regulation. HLA-G tetramers, for example, are involved in immune tolerance, particularly during pregnancy. HLA-G expression on trophoblasts helps to protect the fetus from maternal immune attack by interacting with inhibitory receptors on NK cells and T cells. This immune modulatory function is critical for maintaining a healthy pregnancy and preventing autoimmune responses.

Non-Classical MHC Tetramers in Health

Infection

Non-classical MHC tetramers play vital roles in the immune response to infections. For instance, HLA-E tetramers can present viral peptides to NK cells, enhancing their ability to recognize and eliminate infected cells. This mechanism is particularly important in viral infections where pathogens downregulate classical MHC molecules to evade immune detection. By presenting conserved viral peptides, non-classical MHC molecules ensure the immune system can still identify and respond to infected cells.

Cancer

In the context of cancer, non-classical MHC tetramers offer promising therapeutic avenues. Tumors often exploit immune checkpoints and inhibitory pathways to evade immune surveillance. HLA-G tetramers, which interact with inhibitory receptors on immune cells, are frequently upregulated in various cancers. Understanding this interaction has led to the development of strategies to block HLA-G mediated immune suppression, enhancing the anti-tumor immune response. Additionally, non-classical MHC tetramers can be used to identify tumor-specific T cells, facilitating the development of targeted immunotherapies.

Autoimmunity and Tolerance

Non-classical MHC tetramers are also implicated in autoimmune diseases and immune tolerance. For example, the expression of HLA-G and its interaction with immune inhibitory receptors is associated with the regulation of autoimmune responses. By promoting tolerance, non-classical MHC molecules help to prevent excessive immune activation that can lead to tissue damage in autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.

Non-Classical MHC Tetramers in Disease

Viral Infections

In viral infections, pathogens often evolve mechanisms to evade classical MHC-mediated immune responses. Non-classical MHC molecules provide an alternative pathway for immune recognition. For instance, HCMV (human cytomegalovirus) downregulates classical MHC class I molecules to avoid detection by cytotoxic T lymphocytes (CTLs). However, HLA-E tetramers can present viral peptides to NK cells, compensating for the loss of classical MHC presentation and maintaining immune pressure on the virus.

Cancer Immune Evasion

Cancer cells frequently upregulate non-classical MHC molecules to escape immune detection. HLA-G expression, for example, is associated with poor prognosis in various cancers, including ovarian, breast, and colorectal cancers. By interacting with inhibitory receptors on immune cells, HLA-G tetramers suppress anti-tumor immune responses, facilitating tumor growth and metastasis. Understanding these interactions has prompted the development of therapeutic strategies aimed at blocking HLA-G and restoring effective immune surveillance.

Autoimmune Diseases

Autoimmune diseases result from an imbalance in immune regulation, where the immune system mistakenly targets self-tissues. Non-classical MHC molecules like HLA-G play a protective role by promoting immune tolerance. In diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis, altered expression of HLA-G has been observed. Therapeutic modulation of HLA-G expression and function holds potential for restoring immune balance and mitigating autoimmune pathology.

Emerging Trends and Future Directions

Novel Tetramer Technologies

Recent advancements in tetramer technology have expanded the capabilities of non-classical MHC tetramers. Innovations include the development of multi-antigen tetramers, which can present multiple antigens simultaneously, enhancing the detection of diverse T cell populations. Additionally, improvements in tetramer stability and affinity have increased their utility in clinical and research settings.

Immunotherapy Applications

The unique properties of non-classical MHC tetramers make them attractive candidates for immunotherapy. By targeting specific immune pathways and cell populations, non-classical MHC tetramers can be used to design personalized immunotherapies for cancer and autoimmune diseases. For example, blocking HLA-G interactions or enhancing HLA-E-mediated immune responses are promising strategies for boosting anti-tumor immunity and regulating autoimmune reactions.

Biomarker Discovery

Non-classical MHC tetramers hold potential as biomarkers for disease diagnosis and prognosis. Elevated levels of HLA-G, for instance, are associated with poor outcomes in cancer patients. Monitoring non-classical MHC tetramer expression and function can provide valuable insights into disease progression and treatment efficacy. As research advances, the identification of novel biomarkers will enhance our ability to diagnose and treat various immune-related conditions.

Conclusion

Non-classical MHC tetramers represent a fascinating and rapidly evolving field in immunology. Their unique structural and functional characteristics distinguish them from classical MHC molecules, offering new insights into immune regulation and disease mechanisms. From infection and cancer to autoimmunity and tolerance, non-classical MHC tetramers play pivotal roles in health and disease. Emerging trends in tetramer technology, immunotherapy, and biomarker discovery promise to unlock new therapeutic possibilities and improve our understanding of the immune system. As research continues to unfold, non-classical MHC tetramers will undoubtedly remain at the forefront of immunological innovation.