Posts Tagged ‘autoimmune disease’

Regulatory T cells (Tregs) are important for sperm tolerance and male fertility

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Regulatory T cells (Tregs) are specialized immune cells that modulate tissue homeostasis. They are a specialized subset of T lymphocytes that function as suppressive immune cells and inhibit various elements of immune response in vitro and in vivo. While there are constraints on the number or function of Tregs which can be exploited to evoke an effective anti-tumor response, sufficient expansion of Tregs is essential for successful organ transplantation and for promoting tolerance of self and foreign antigens. Current studies have provided evidence that a defect in the number or function of Tregs contributes to the etiology of several reproductive diseases.

In the male reproductive tract, prevention of autoimmune responses against antigenic spermatozoa, while ensuring protection against stressors, is a key determinant of fertility. Using an autoimmunity-induced model, it was uncovered that the role of Tregs in maintaining the tolerogenic state of the testis and epididymis. The loss of tolerance induced an exacerbated immune cell infiltration and the development of anti-sperm antibodies, which caused severe male subfertility. By identifying immunoregulatory mechanisms in the testis and epididymis.

Tregs modulate tissue homeostatic processes and immune responses. Understanding tissue-Treg biology will contribute to developing precision-targeting treatment strategies. Here, it was reported that Tregs maintain the tolerogenic state of the testis and epididymis, where sperm are produced and mature. It was found that Treg depletion induces severe autoimmune orchitis and epididymitis, manifested by an exacerbated immune cell infiltration [CD4 T cells, monocytes, and mononuclear phagocytes (MPs)] and the development of anti-sperm antibodies (ASA).

In Treg-depleted mice, MPs increased projections toward the epididymal lumen as well as invading the lumen. ASA-bound sperm enhance sperm agglutination and might facilitate sperm phagocytosis. Tolerance breakdown impaired epididymal epithelial function and altered extracellular vesicle cargo, both of which play crucial roles in the acquisition of sperm fertilizing ability and subsequent embryo development. The affected mice had reduced sperm number and motility and severe fertility defects.

Deciphering these immunoregulatory mechanisms may lead to the development of therapies for infertility and identifying potential targets for immuno-contraception. Ultimately, such knowledge fills gaps related to reproductive mucosa, which is an understudied facet of human male health.







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RNA Testing

Curator: Larry H. Bernstein, MD, FCAP



RNA Testing: A Fast, Accurate Tool for Diagnosing Autoimmune Disease

05/17/2016 –   Dr. Chase Spurlock, IQuity CEO and Dr. Thomas Aune, IQuity Chief Science Officer

Diagnosing complex autoimmune diseases and related conditions is a challenging endeavor, as these multifaceted conditions often present with non-specific symptoms across several organ systems. Historically, physicians have diagnosed autoimmune disease through detailed physical examination, collection of medical and family history, multiple laboratory tests and monitoring symptoms over time. Current diagnostic algorithms can lead to a protracted and costly diagnostic process of elimination.

However, emerging RNA-based diagnostic technologies can dramatically reduce the time to diagnosis of complex diseases, including autoimmune disease. With the completion of the Human Genome Project and basic research in the field of RNA biology over the past two decades, it is now accepted that the majority of the human genome is transcribed into unique patterns of information that exhibit cell type specificity and are consistent in a variety of chronic conditions, including autoimmune disease. With the invention of new technologies, including next-generation RNA sequencing, we are able to assess global changes in gene expression.

As such, RNA-based tools are now poised to provide physicians with actionable information early in the diagnostic process. While RNA-based testing is a relatively new innovation in the clinical setting and widespread adoption efforts are still in their infancy, the science behind these techniques makes them a reliable method for helping physicians make fast, accurate decisions.

The science behind RNA

Analysis of RNA expression paints a molecular portrait of what’s going on in an individual’s cells at a given point in time. This can provide a picture of disease manifestation. At a high level, current RNA testing involves collecting a patient’s blood sample via standard venipuncture, isolating the RNA and then detecting RNA expression patterns in real time using polymerase chain reaction (PCR). The turning on or off of these expression patterns can serve as an indicator of the presence or absence of disease.

In contrast, DNA tests examine changes in nucleotide sequence to establish a patient’s risk of developing a particular condition. These genotype associations do not always reveal information about disease manifestation. A DNA test, for example, might indicate that a patient is at high risk for an autoimmune disorder, such as rheumatoid arthritis (RA) or multiple sclerosis (MS), but the patient may never develop the condition. Just because the patient has a particular DNA risk marker does not mean he or she actually has—or will have—the disease. Thus, a major limitation with DNA methodology is its inability to reliably forecast active disease. RNA tests are more specific in this regard.

Other types of testing, such as pharmacologic and serologic testing, have also been used to detect autoimmune disorders. However, due to the complexity of these diseases, a single test can only put a physician one small step closer to diagnosis and additional tests are often required. For instance, to accurately identify RA, a clinician may need to perform approximately 10 to 15 different molecular tests over what is often a lengthy time period. If the doctor concludes that a portion of these tests point to the presence of RA, then he or she may be able to make a diagnosis of RA. In some cases, it can take years for the patient to receive a definitive diagnosis. In comparison, new RNA-based diagnostic testing for the same condition offers an accuracy of greater than 90 percent, enabling a higher degree of certainty for establishing the presence or absence of the disease.

The impact on patients, providers and the scientific community

As RNA testing becomes more widespread, its impact on patients, providers and other stakeholders promises to be significant. Once widely adopted, this kind of testing could cut down on the number of tests and amount of the time needed to confirm diagnosis. This, in turn, would enhance the patient experience, as individuals would no longer have to undergo repeated or invasive testing to determine if they have a disease.

Current autoimmune therapies are reasonably effective at slowing disease advancement.  Across many autoimmune diseases, the best outcomes are achieved when therapies are initiated early in the disease process. Providing physicians with actionable diagnostic information enables the provider to place patients on the appropriate treatments faster, limiting disease progression and supporting better long-term health outcomes.

RNA testing can improve outcomes for providers by helping to get patients on the path to suitable treatment earlier. This not only facilitates optimal medication performance, but also lessens the cost of diagnosis and management of disease.  In turn, this ensures a better quality of life for patients.

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Controlling CAR-T cells

Larry H. Bernstein, MD, FCAP, Curator



New discovery – Remote control of CAR-T cells

T cells, Cancer immune therapy, autoimmune

CAR-T cells have been emerging as an effective approach to treat cancer and autoimmune diseases. A problem with CAR-T cells is that once they are infused, they are on their own exerting autonomous activities, which can lead to severe side effects due to the extensive lysis of tumor cells. Researchers have been seeking ways to control CAR-T cells after they are infused to balance the desired therapeutic effect and the side effect. Recently, a group of researchers at UCSF found a way to control CAR-T cells after they are put into patients, through a rapamycine analogue gated chimeric receptor.

CAR-T cell system has two components: one is the recognition domain that binds to CD19 to target B cells; the other is the functional domain to activate cellular pathways to killing the targeted cells. Those two domains are typically preassembled. What this group of researchers did is to separate those two domains and make them come together only in the presence of the activating molecule, a rapamycine analogue. They showed that in the absence of the activating molecule, CAR-T cells still bound to CD19. But, they didn’t kill the targeted cells unless the activating molecule was present. In addition, by adjusting the dose of the activating molecule, the strength of CAR-T cells activities can be titrated as well.

Chia-Yung Wu, etc. (October 2015) Remote control of therapeutic T cells through a small molecule–gated chimeric receptor.Science


Remote control of therapeutic T cells through a small molecule–gated chimeric receptor




Reengineering Therapeutics

Larry H. Bernstein, MD, FCAP, Curator


The synNotch solution: UCSF scientists engineer a next-gen T-cell immunotherapy

Sunday, January 31, 2016 | By John Carroll

CAR-T has been all the rage in cancer R&D for several years now as a slate of biotech upstarts pursue highly promising work reengineering T cells into attack weapons by adding a chimeric antigen receptor that can zero in on particular cancer cells. The approach has been highly effective in acute lymphoblastic leukemia, triggering an attack on B cells by homing in on the CD19 antigen, a breakthrough that has inspired a race to the regulatory finish line with the first CAR-Ts.



Regulatory DNA engineered

Larry H. Bernstein, MD, FCAP, Curator



New Type of CRISPR Screen Probes the Regulatory Genome

Aaron Krol    http://www.bio-itworld.com/2016/2/8/new-type-crispr-screen-probes-regulatory-genome.html

February 8, 2016 | When a geneticist stares down the 3 billion DNA base pairs of the human genome, searching for a clue to what’s gone awry in a single patient, it helps to narrow the field. One of the most popular places to look is the exome, the tiny fraction of our DNA―less than 2%―that actually codes for proteins. For patients with rare genetic diseases, which might be fully explained by one key mutation, many studies sequence the whole exome and leave all the noncoding DNA out. Similarly, personalized cancer tests, which can help bring to light unexpected treatment options, often sequence the tumor exome, or a smaller panel of protein-coding genes.


sjwilliamspa commented on Controlling CAR-T cells

Controlling CAR-T cells Larry H. Bernstein, MD, FCAP, Curator LPBI New discovery – Remote control of CAR-T cells CAR-T …

Interesting method to use a chimeric heterodimer receptor to control CD19 activity however it would be ineresting to see if cancer replapses occur more frequently. Originally it was thought the CART would act, after initial treatment, eventually to patrol the body for any recurring tumor cells. Using rapamycin would be interesting although there had been some immunotoxic concerns with chronic use (although long term use of rapamycin and other mtor inhibitors seemed to prolong lifespan in immunodeficient animals)

Temsirolimus, an Inhibitor of Mammalian Target of Rapamycin athttp://clincancerres.aacrjournals.org/content/14/5/1286.short

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